LPS Cholesterol

lps inflammation macrophage cholesterol - PubMed - NCBI
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lps inflammation macrophage cholesterol
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Results: 55
J Endocrinol. 2012 Oct 11. [Epub ahead of print]
1.
TLR4 Antagonist Reduces Early-Stage Atherosclerosis in Diabetic Apolipoprotein E-deficient Mice.

Lu Z, Zhang X, Li Y, Jin J, Huang Y.
Z Lu, Medicine, Medical University of South Carolina, Charleston, United States.
Abstract
Although it has been reported that deficiency of toll-like receptor (TLR)4 is associated with reduced atherosclerosis in atherosclerosis-prone mice and attenuated pro-inflammatory state in diabetic mice, it remains undetermined if treatment with TLR4 antagonist reduces atherosclerosis in non-diabetic or diabetic mice that have TLR4 expression. In this study, we determined the effect of R. sphaeroides LPS (Rs-LPS), an established TLR4 antagonist, on the early-stage atherosclerosis in non-diabetic and streptozotocin-induced diabetic apolipoprotein E-deficient (apoE-/-) mice. Analysis of atherosclerotic lesions of both en face aortas and cross-sections of aortic roots showed that administration of RsLPS in 14 week-old diabetic apoE-/- mice for 10 weeks significantly reduced atherosclerotic lesions. Although atherosclerotic lesions in non-diabetic apoE-/- mice appeared to be decreased by Rs-LPS treatment, the difference was not statistically significant. Metabolic study showed that Rs-LPS significantly lowered serum levels of cholesterol and triglycerides in non-diabetic mice, but not diabetic mice. Furthermore, immunohistochemistry studies showed that Rs-LPS inhibited the expression of interleukin6 and matrix metalloproteinase-9 and reduced the content of monocytes and macrophages in atherosclerotic plaques. Taken together, this study demonstrated for the first time that TLR4 antagonist inhibited vascular inflammation and atherogenesis in diabetic apoE-/- mice and lowered serum cholesterol and triglyceride levels in nondiabetic apoE-/- mice.
PMID: 23060524 [PubMed - as supplied by publisher]
Biochim Biophys Acta. 2012 Dec;1821(12):1485-92. doi: 10.1016/j.bbalip.2012.08.011. Epub 2012 Aug 23.
2.
Advanced glycated albumin impairs HDL anti-inflammatory activity and primes macrophages for inflammatory response that reduces reverse cholesterol transport.
Okuda LS, Castilho G, Rocco DD, Nakandakare ER, Catanozi S, Passarelli M.
Lipids Laboratory (LIM 10), University of So Paulo Medical School, So Paulo, SP, Brazil.
http://www.ncbi.nlm.nih.gov/pubmed
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Abstract
Objective: We investigated the effect of advanced glycated albumin (AGE-albumin) on macrophage sensitivity to inflammation elicited by S100B calgranulin and lipopolysaccharide (LPS) and the mechanism by which HDL modulates this response. We also measured the influence of the culture medium, isolated from macrophages treated with AGE-albumin, on reverse cholesterol transport (RCT). Methods and results: Macrophages were incubated with control (C) or AGE-albumin in the presence or absence of HDL, followed by incubations with S100B or LPS. Also, culture medium obtained from cells treated with C- or AGE-albumin, following S100B or LPS stimulation was utilized to treat naive macrophages in order to evaluate cholesterol efflux and the expression of HDL receptors. In comparison with C-albumin, AGE-albumin, promoted a greater secretion of cytokines after stimulation with S100B or LPS. A greater amount of cytokines was also produced by macrophages treated with AGE-albumin even in the presence of HDL. Cytokine-enriched medium, drawn from incubations with AGE-albumin and S100B or LPS impaired the cholesterol efflux mediated by apoA-I (23% and 37%, respectively), HDL(2) (43% and 47%, respectively) and HDL(3) (20% and 8.5%, respectively) and reduced ABCA-1 protein level (16% and 26%, respectively). Conclusions: AGE-albumin primes macrophages for an inflammatory response impairing the RCT. Moreover, AGE-albumin abrogates the anti-inflammatory role of HDL, which may aggravate the development of atherosclerosis in DM. Copyright 2012 Elsevier B.V. All rights reserved.
PMID: 22940078 [PubMed - in process]
Inflammation. 2012 Aug;35(4):1530-7.
3.
Lipopolysaccharide-induced proliferation of the vasa vasorum in a rabbit model of atherosclerosis as evaluated by contrast-enhanced ultrasound imaging and histology.
Tian J, Hu S, Han X, Dong N, Yu H, Sun Y, Yu B.
Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.
Abstract
Whether lipopolysaccharide (LPS) can promote vasa vasorum (VV) proliferation for atherosclerosis in vivo is unclear. Eighteen rabbits with atherosclerosis were randomly assigned into one of three groups of six. Group A received biweekly injections of 10 mL saline after 2 weeks of balloon injury. Groups B and C received biweekly intravenous injections of 3.0 g LPS in 10 mL saline at weeks 10 and 4, respectively, until study termination. LPS significantly increased the levels of triglycerides and C-reactive protein and decreased the level of high-density lipoprotein cholesterol. Group C had significant larger plaques and more macrophages than group A (p = 0.01 and p < 0.001, respectively). Contrast enhancement ultrasound imaging and histological detection
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demonstrated that plaques in group C had a significantly higher VV density than that in group A (p = 0.009 and p = 0.002, respectively). In summary, VV proliferation for plaque destabilization can be accelerated by LPS-induced systemic inflammation and changes in lipid profiles.
Publication Types
Publication Types Research Support, Non-U.S. Gov't
Vascul Pharmacol. 2012 Aug 19;57(1):56-64. Epub 2012 Mar 20.
4.
Effect of sphingosine 1-phosphate (S1P) receptor agonists FTY720 and CYM5442 on atherosclerosis development in LDL receptor deficient (LDL-R/) mice.
Poti F, Costa S, Bergonzini V, Galletti M, Pignatti E, Weber C, Simoni M, Nofer JR.
Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy.
Abstract
OBJECTIVES: Sphingosine 1-phosphate (S1P)--a lysosphingolipid present in HDL-exerts atheroprotective effects in vitro, while FTY720, a non-selective S1P mimetic inhibits atherosclerosis in LDL receptor-deficient (LDL-R/) mice under conditions of severe hypercholesterolemia. We here examined the effect of FTY720 and a selective S1P receptor type 1 agonist CYM5442 on atherosclerosis in moderately hypercholesterolemic LDL-R/ mice. METHODS AND RESULTS: LDL-R/ mice fed Western diet (0.25% cholesterol) were given FTY720 (0.4 mg/kg/day) or CYM5442 (2.0 mg/kg/day) for 18 weeks. FTY720 but not CYM5422 persistently lowered blood lymphocytes, depleted CD4 and CD8 T cells in spleen and lymph nodes, and reduced splenocyte IL-2 secretion. However, both compounds reduced the activity of splenic and peritoneal macrophages as inferred from the down-regulated CD68 and MHC-II expression in CD11b cells and the reduced IL-6 secretion in response to LPS, respectively. CYM5442 and FTY720 reduced weight gain, white adipose tissue depots and fasting glucose suggesting improvement of metabolic control, but failed to influence atherosclerosis in LDL-R/ mice. CONCLUSION: Despite down-regulating macrophage function and--in case of FTY720-altering lymphocyte distribution CYM5442 and FTY720 fail to affect atherosclerosis in moderately hypercholesterolemic LDL-R/ mice. We hypothesize that S1P mimetics exert atheroprotective effects only under conditions of increased cholesterol burden exacerbating vascular inflammation.
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Copyright 2012 Elsevier Inc. All rights reserved.

Publication Types
Mol Hum Reprod. 2012 Jul;18(7):341-53. Epub 2012 Jan 10.
5.
Oxysterols exert proinflammatory effects in placental trophoblasts via TLR4-dependent, cholesterol-sensitive activation of NF-B.
Aye IL, Waddell BJ, Mark PJ, Keelan JA.
School of Women's and Infants' Health, Faculty of Medicine, Dentistry and Health Sciences, King Edward Memorial Hospital, 374 Bagot Rd, Subiaco, The University of Western Australia, Perth, WA 6008, Australia. iaye@meddent.uwa.edu.au
Abstract
Oxidized cholesterol metabolites (oxysterols) promote inflammation in a variety of cell types and are thought to be involved in a number of disease pathologies. Oxysterol concentrations are increased in pregnancy, together with systemic oxidative stress and inflammation. We tested the hypothesis that oxysterols 25-hydroxycholesterol (25-OHC) and 7-ketocholesterol (7-ketoC) promote placental trophoblast inflammation, and determined the mechanisms involved. Treatment of primary trophoblasts in culture with 25 -OHC and 7-ketoC increased the production of proinflammatory cytokines (interleukin-6, macrophage inflammatory protein-1 and tumour necrosis factor-) in a concentrationdependent fashion. Inhibition of TLR4 activation using selective inhibitors of TLR4 complex formation (OxPAPC) or signalling transmission (CLI095) prevented lipopolysaccharide (LPS)- and oxysterol-induced inflammatory cytokine production. Pretreatment of trophoblasts with selective inhibitors of I-kB kinase activity (parthenolide and TPCA-1) reduced oxysterol- and LPS-stimulated inflammatory responses, consistent with the involvement of the nuclear factor kappa B (NF-B) pathway downstream of TLR4 signalling. Both oxysterols also increased the phosphorylation and nuclear localization of NF-B subunit p65/RelA. Oxysterols are also known to activate liver X receptors (LXRs) which can inhibit inflammatory signalling, either directly or indirectly via membrane cholesterol reduction. Treatment with the LXR agonist, T0901317, exerted significant anti -inflammatory effects, reducing LPS- and oxysterol-driven cytokine production. Treatment with methyl--cyclodextrin to deplete membrane microdomain cholesterol and thereby disrupt TLR4 signalling, similarly abrogated their effects. Together, these findings indicate that although oxysterols likely activate both pro- and anti-inflammatory pathways in the placenta, the predominant effect is the promotion of placental inflammation via TLR4dependent activation of NF-B.
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Publication Types
J Atheroscler Thromb. 2011;18(12):1117-26. Epub 2011 Oct 18.
6.
Melittin inhibits atherosclerosis in LPS/high-fat treated mice through atheroprotective actions.

Kim SJ, Park JH, Kim KH, Lee WR, Kim KS, Park KK.
Department of Pathology, School of Medicine, Catholic University of Daegu, Daegu, South Korea.
Abstract
AIM: Atherosclerosis is influenced by multiple environmental factors that involve a complex interaction between blood components and the arterial wall and is characterized by inflammatory reactions. Melittin has been used in treatment of various chronic inflammatory diseases. We investigated the effects of melittin regulated atherosclerotic changes in an animal model of atherosclerosis. METHODS: Atherosclerotic mice were induced by intraperitoneal (i.p) injection of lipopolysaccharide (LPS, 2 mg/kg) three times a week and an atherogenic diet for 12 weeks. RESULTS: Melittin (0.1 mg/kg) treatment was administered with i.p injection. Melittin treatment showed that total cholesterol and triglyceride levels decreased in atherosclerotic mice however, high-density lipoprotein cholesterol (HDL-C) levels were higher in atherosclerotic mice treated with melittin than in atherosclerotic mice. H&E staining showed that heart and descending aorta were significantly recovered by melittin, compared to atherosclerotic mice. In addition, melittin decreased the expression levels of tumor necrosis factor (TNF)-, interleukin (IL)-1, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, fibronectin and transforming growth factor (TGF)-1 in atherosclerotic mice. In vitro, melittin decreased LPS-induced THP-1 cells-derived macrophages TNF- and IL-1 expression levels and nuclear factor (NF)B signal pathway. CONCLUSIONS: These results demonstrate that melittin has an anti-atherogenic effect by suppression of pro-inflammatory cytokines and adhesion molecules.
PMID: 22008474 [PubMed - indexed for MEDLINE] Free full text
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Publication Types, MeSH Terms, Substances

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals Atherosclerosis/metabolism Atherosclerosis/prevention & control* Blotting, Western Cell Line Cytokines/metabolism Dietary Fats/administration & dosage* Enzyme-Linked Immunosorbent Assay Humans Inflammation Mediators/metabolism Lipopolysaccharides/administration & dosage* Male Melitten/pharmacology* Mice Mice, Inbred BALB C Substances Cytokines Dietary Fats Inflammation Mediators Lipopolysaccharides Melitten
Shock. 2011 Nov;36(5):484-93.
7.
The immunologic outcome of enhanced function of mouse liver lymphocytes and Kupffer cells by high-fat and highcholesterol diet.
Shono S, Habu Y, Nakashima M, Sato A, Nakashima H, Miyazaki H, Kinoshita M, Tsumatori G, Shinomiya N, Seki S.
Department of Immunology and Microbiology, National Defense Medical College and Division of Traumatology, National Defense Medical College Research Institute, Tokorozawa, Japan.
Abstract
Dietary lipids/cholesterol may modulate liver immune function. We have recently found that mouse F4/80 Kupffer cells are classified into phagocytic CD68 Kupffer cells and cytokine-producing CD11b Kupffer cells. We here investigate how a high-fat and/or high-
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cholesterol diet affects innate immune liver mononuclear cells. For 4 weeks, C57BL/6 mice were fed a high-fat and high-cholesterol diet (HFCD), a high-cholesterol diet (HCD), a high-fat diet (HFD), or a control diet (CD). High-fat and high-cholesterol diet and HCD increased liver cholesterol levels; serum cholesterol levels increased in HFCD and HFD mice but not in HCD mice. The increased proportion of natural killer (NK) cells, downregulated NK1.1 expression of natural killer T cells, and enhanced CD69 and IL-12 receptor mRNA expression of liver lymphocytes indicate the activation of them by HFCD. IL-12 production from Kupffer cells and interferon production from NK/natural killer T cells activated by LPS and/or IL-12 both increased. IL-12 pretreatment more effectively improved the survival of HFCD mice relative to the survival of CD mice upon injections of liver metastatic EL-4 cells. In contrast, HFCD mouse survival decreased after LPS injection and generalized Shwartzman reaction. Consistently in HFCD mice, Toll-like receptor 4 mRNA expression of whole Kupffer cells was upregulated, and CD11b Kupffer cells proportionally increased. Although the proportion of CD68 Kupffer cells decreased in HFCD mice, phagocytic activity of them was enhanced. Mice fed with HCD rather than those fed with HFD showed features closer to HFCD mice. Thus, enhanced function of mouse liver mononuclear cells is likely dependent on the liver cholesterol level, rather than the liver triglyceride level.
PMID: 21937954 [PubMed - indexed for MEDLINE]
MeSH Terms, Substances

MeSH Terms Animals Cholesterol/blood Cholesterol/metabolism Diet, High-Fat* Interleukin-12/metabolism Killer Cells, Natural/drug effects Killer Cells, Natural/metabolism Kupffer Cells/drug effects Kupffer Cells/metabolism* Lipopolysaccharides/pharmacology Liver/cytology* Liver/drug effects Liver/immunology Lymphocytes/drug effects Lymphocytes/metabolism* Male Mice Mice, Inbred C57BL Receptors, Interleukin-12/genetics
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Shock, Septic/chemically induced Shock, Septic/immunology Shock, Septic/metabolism Triglycerides/blood Triglycerides/metabolism Substances Lipopolysaccharides Receptors, Interleukin-12 Triglycerides Interleukin-12 Cholesterol
J Agric Food Chem. 2011 Sep 28;59(18):10381-7. Epub 2011 Sep 1.
8.
Phenolic acids are in vivo atheroprotective compounds appearing in the serum of rats after blueberry consumption.
Xie C, Kang J, Chen JR, Nagarajan S, Badger TM, Wu X.
USDA Arkansas Children's Nutrition Center, Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, 15 Children's Way, Little Rock, Arkansas 72202, United States.
Abstract
Blueberries (BB) have recently been shown to have cardioprotective effects and to prevent atherosclerosis in rodent models. However, the bioactive compounds in BB responsible for these effects have not yet been characterized. Seven phenolic acids (7PA) were identified as metabolites in the serum of rats fed diets supplemented with 10% freeze-dried BB. In this study, 7PA were evaluated for their potential atheroprotective effects in murine macrophage cell line RAW 264.7. 7PA were found to inhibit LPSinduced mRNA expression and protein levels of pro-inflammatory cytokine TNF- and IL-6 by reducing MAPK JNK, p38, and Erk1/2 phosphorylation. After treatment with 7PA for 2 weeks, mRNA expression and protein levels of scavenger receptor CD36 were decreased (P<0.05), whereas type A scavenger receptor (SR-A) remained unchanged. Moreover, foam cell formation induced by oxLDL and oxLDL binding to macrophages was also inhibited by 7PA. In addition, 7PA increased (P<0.05) expression and protein levels of ATP-binding cassette transporter A1 (ABCA1), which facilitates cholesterol efflux and reduces cholesterol accumulation in macrophages. In summary, the present study demonstrates that certain phenolic acids are potential in vivo atheroprotective compounds following BB consumption in the rodent model. Because BB contain many phytochemicals, other as yet unidentified bioactive compounds may also be important in preventing atherosclerosis in this model and, possibly, in humans.
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Publication Types Research Support, U.S. Gov't, Non-P.H.S. MeSH Terms Acids, Carbocyclic/administration & dosage* Acids, Carbocyclic/pharmacology Animals Atherosclerosis/prevention & control* Blueberry Plant/chemistry* Cell Line Coumaric Acids Cytokines/antagonists & inhibitors Diet* Fruit/chemistry* Inflammation/prevention & control Macrophages/drug effects Macrophages/metabolism Mice Rats Receptors, Scavenger/antagonists & inhibitors Substances Acids, Carbocyclic Coumaric Acids Cytokines Receptors, Scavenger ferulic acid
Br J Nutr. 2011 Nov;106(9):1416-22. Epub 2011 Jun 28.
9.
Reduction of monocyte chemoattractant protein 1 and macrophage migration inhibitory factor by a polyphenol-rich extract in subjects with clustered cardiometabolic risk factors.
Broekhuizen LN, van Wijk DF, Vink H, Stalmach A, Crozier A, Hutten BA, Kastelein JJ, Hugenholtz PG, Koenig W, Stroes ES.
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Abstract
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Inflammation is a hallmark of the metabolic syndrome, which also contributes to a proatherogenic state. NF-B activation, a critical step in regulating inflammatory reactions, can be inhibited by polyphenol (PF) extracts, at least in vitro. In the present study, we set out to study whether a PF-rich extract could attenuate the chronic inflammatory state and/or an acute immune response in vivo in subjects with clustered metabolic risk factors. A commercially available, PF-rich extract (500 mg daily) or placebo was administered for 4 weeks to thirty-four subjects with two or more metabolic risk factors using a randomised, double-blind, cross-over design. During the final study visit, an acute inflammatory challenge (lipopolysaccharide (LPS) 1 ng/kg body weight) was administered to a random subgroup of subjects (PF-rich extract (n 12) and placebo (n 12)). The PF-rich extract modestly reduced the inflammatory chemokines monocyte chemoattractant protein 1 (MCP-1) and macrophage migration inhibitory factor (MIF) (MCP-1 - 6.5 % (PF, median 116 (interquartile range 97-136) pg/ml v. placebo, median 124 (interquartile range 105153) pg/ml; P < 0.05); MIF - 10.8 % (PF, median 2512 (interquartile range 1898-3972) pg/ml v. placebo, median 2814.5 (interquartile range 2296-3852) pg/ml; P < 0.05); however, other measured markers of inflammation and cardiometabolic disease, such as C-reactive protein, IL-6, HDL-cholesterol, adiponectin and oxidised LDL, remained unaffected. Following the LPS challenge, we found a statistically significant 48 % reduction of MCP-1 production in the PF-rich extract group (n 12) v. placebo (n 12) over 6 h (PF 766 (sd 155) v. placebo 1466 (sd 989) ng/ml; P < 0.05, area under the curve). In conclusion, short-term oral administration of the PF-rich extract caused a modest antiinflammatory effect in subjects with clustered metabolic risk factors. Further dose-ranging studies are needed to evaluate whether and to what extent PF-rich extracts can be used to reduce the pro-inflammatory state in subjects with metabolic diseases at increased cardiovascular risk.

Publication Types Randomized Controlled Trial Research Support, Non-U.S. Gov't MeSH Terms Aged Biological Markers/blood Chemokine CCL2/blood* Cross-Over Studies Double-Blind Method Humans Immunity Inflammation/blood
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Inflammation/drug therapy* Inflammation Mediators/blood* Lipopolysaccharides Macrophage Migration-Inhibitory Factors/blood* Metabolic Syndrome X/etiology Metabolic Syndrome X/prevention & control* Middle Aged Phytotherapy Plant Extracts/pharmacology Plant Extracts/therapeutic use* Polyphenols/pharmacology Polyphenols/therapeutic use* Risk Factors Substances Biological Markers Chemokine CCL2 Inflammation Mediators Lipopolysaccharides Macrophage Migration-Inhibitory Factors Plant Extracts Polyphenols
PLoS One. 2011;6(5):e20240. Epub 2011 May 19.
10.
Chronic oral infection with Porphyromonas gingivalis accelerates atheroma formation by shifting the lipid profile.
Maekawa T, Takahashi N, Tabeta K, Aoki Y, Miyashita H, Miyauchi S, Miyazawa H, Nakajima T, Yamazaki K.
Center for Transdisciplinary Research, Niigata University, Niigata, Japan.
Abstract
BACKGROUND: Recent studies have suggested that periodontal disease increases the risk of atherothrombotic disease. Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in the arteries. Although several studies have suggested that certain periodontopathic bacteria accelerate atherogenesis in apolipoprotein E-deficient mice, the mechanistic link between cholesterol accumulation and periodontal infection-induced inflammation is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We orally infected C57BL/6 and C57BL/6.KOR -Apoe(shl) (B6.Apoeshl) mice with Porphyromonas gingivalis, which is a representative periodontopathic bacterium, and evaluated atherogenesis, gene expression in the aorta and liver and systemic inflammatory and lipid profiles in the blood. Furthermore, the effect
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of lipopolysaccharide (LPS) from P. gingivalis on cholesterol transport and the related gene expression was examined in peritoneal macrophages. Alveolar bone resorption and elevation of systemic inflammatory responses were induced in both strains. Despite early changes in the expression of key genes involved in cholesterol turnover, such as liver X receptor and ATP-binding cassette A1, serum lipid profiles did not change with short-term infection. Long-term infection was associated with a reduction in serum high-density lipoprotein (HDL) cholesterol but not with the development of atherosclerotic lesions in wild-type mice. In B6.Apoeshl mice, long-term infection resulted in the elevation of very low-density lipoprotein (VLDL), LDL and total cholesterols in addition to the reduction of HDL cholesterol. This shift in the lipid profile was concomitant with a significant increase in atherosclerotic lesions. Stimulation with P. gingivalis LPS induced the change of cholesterol transport via targeting the expression of LDL receptor-related genes and resulted in the disturbance of regulatory mechanisms of the cholesterol level in macrophages. CONCLUSIONS/SIGNIFICANCE: Periodontal infection itself does not cause atherosclerosis, but it accelerates it by inducing systemic inflammation and deteriorating lipid metabolism, particularly when underlying hyperlidemia or susceptibility to hyperlipidemia exists, and it may contribute to the development of coronary heart disease.
PMID: 21625524 [PubMed - indexed for MEDLINE] PMCID: PMC3098290 Free PMC Article

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals Gene Expression Profiling Lipids/blood* Mice Mice, Inbred C57BL Mouth Diseases/microbiology* Plaque, Atherosclerotic/microbiology* Porphyromonas gingivalis/isolation & purification Porphyromonas gingivalis/physiology* Substances Lipids
J Surg Res. 2012 May 15;174(2):344-51. Epub 2011 Jan 22.
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11.
Acute acalculous cholecystitis-like phenotype in scavenger receptor A knock-out mice.

Drummond R, Song D, Hawisher D, Wolf PL, Vazquez DE, Nino DF, Coimbra R, Cauvi DM, De Maio A.
Department of Surgery, University of California San Diego, La Jolla, California 92093, USA.
Abstract
BACKGROUND: Sepsis is a major health problem in the United States that affects more than three-quarters of a million people every year. Previous studies have shown that scavenger receptor A (Sra), also known as macrophage scavenger receptor 1 (Msr1), is a modifier of interleukin 10 (IL-10) expression after injection of bacterial lipopolysaccharide (LPS). Therefore, we investigated the response to sepsis in Sra knock out mice. MATERIALS AND METHODS: C57BL/6J (B6) (n = 88) and Sra (-/-) mice (n = 88) were subjected to cecal ligation and puncture (CLP) using 18G or 16G needles, sham operation, or non-operated controls. At the end, mice were autopsied for the determination of abnormalities after the procedure. Cytokine gene expression was examined in lung and liver samples by quantitative RT-PCR (qRT-PCR), and circulating cholesterol levels were also measured. RESULTS: Sra (-/-) mice displayed an enlargement of the gallbladder after CLP that was not detected in sham or non-operated mice or in B6 mice (wild-type) after CLP. The enlarged gallbladder resembles a condition of acute acalculous cholecystitis observed in humans. Sra (-/-) mice presented high cholesterol levels in circulation as opposed to wild type B6 mice. Moreover, Sra (-/-) mice exhibited a reduction in IL-10 mRNA levels in lungs compared to wild-type B6 mice after CLP. CONCLUSIONS: The development of acute acalculous cholecystitis may be the combination of pre-existing conditions, such as hypercholesterolemia associated with a defect in Sra (Msr1) and a robust inflammation induced by sepsis. Copyright 2012 Elsevier Inc. All rights reserved.
PMID: 21474146 [PubMed - indexed for MEDLINE] PMCID: PMC3173564 [Available on 2013/5/15]
Publication Types, MeSH Terms, Substances, Grant Support

Publication Types Research Support, N.I.H., Extramural MeSH Terms Acalculous Cholecystitis/etiology* Acalculous Cholecystitis/metabolism Animals Cecum/surgery Cholesterol/blood
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Disease Models, Animal Interleukin-10/metabolism Ligation Lung/metabolism Mice Mice, Inbred C57BL Mice, Knockout Phenotype Scavenger Receptors, Class A/genetics* Sepsis/complications* Sepsis/genetics Sepsis/metabolism Substances IL10 protein, mouse Scavenger Receptors, Class A Interleukin-10 Cholesterol Grant Support GM073825/GM/NIGMS NIH HHS/United States R01 GM073825-04/GM/NIGMS NIH HHS/United States
Microb Pathog. 2011 Sep;51(3):217-24. Epub 2011 Mar 21.
12.
The effect of proatherogenic microbes on macrophage cholesterol homeostasis in apoE-deficient mice.

Tuomainen AM, Hyvrinen K, Ehlers PI, Mervaala E, Leinonen M, Saikku P, Kovanen PT, Jauhiainen M, Pussinen PJ.
Institute of Dentistry, University of Helsinki, FI-00014 Helsinki, Finland.
Abstract
BACKGROUND: Pathogens such as Aggregatibacter actinomycetemcomitans (Aa) and Chlamydia pneumoniae (Cpn) associate with an increased risk for cardiovascular diseases by inducing inflammation. We hypothesized that the pathogens affect the vascular wall by disturbing cholesterol homeostasis and endothelial function. METHODS: Aa- and Cpn-infections were induced in apoE-deficient mice by intravenous and intranasal applications, respectively. Cholesterol efflux from mouse peritoneal macrophages to apo(lipoprotein)A-I was assessed. The efflux capacity of mouse sera as acceptors of cholesterol from RAW264.7-macrophages was determined. Additionally, endothelial function was studied by following the relaxation capacity of rat mesenteric
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arteries after incubation in the conditioned culture media of the peritoneal macrophages isolated from the mice. RESULTS: Infection increased serum phospholipid transfer protein (PLTP) and lipopolysaccharide (LPS) activity, as well as serum amyloid A (SAA) and TNF- concentrations. Peritoneal macrophages of mice with Aa-infection showed increased cholesterol uptake and reduced cholesterol efflux. Sera of Cpn and Cpn + Aa-infected mice had reduced cholesterol efflux capacity from RAW264.7-macrophages. Conditioned macrophage medium from mice with chronic C. pneumoniae infection induced endothelial dysfunction. Additionally, concentrations of serum adhesion molecules, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) in Cpn-groups and E-selectin in Cpn + Aa-group, were elevated. The serum markers of endothelial function correlated positively with SAA. CONCLUSIONS: Aa- and Cpn-infections may generate proatherogenic changes in the vascular wall by affecting the macrophage cholesterol homeostasis and endothelial function. Copyright 2011 Elsevier Ltd. All rights reserved.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals Apolipoproteins E/deficiency* Chlamydophila Infections/microbiology Chlamydophila Infections/pathology Chlamydophila pneumoniae/pathogenicity* Cholesterol/metabolism* Culture Media, Conditioned Disease Models, Animal Endothelial Cells/physiology Homeostasis Lipopolysaccharides/blood Macrophages/metabolism* Macrophages/microbiology* Male Mice Mice, Knockout Pasteurellaceae/pathogenicity*
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Pasteurellaceae Infections/microbiology Pasteurellaceae Infections/pathology Phospholipid Transfer Proteins/blood Rats Serum/chemistry Serum Amyloid A Protein/analysis Tumor Necrosis Factor-alpha/blood Substances Apolipoproteins E Culture Media, Conditioned Lipopolysaccharides Phospholipid Transfer Proteins Serum Amyloid A Protein Tumor Necrosis Factor-alpha Cholesterol
J Atheroscler Thromb. 2011;18(4):282-90. Epub 2010 Dec 10.
13.
Housefly maggots (Musca domestica) protein-enriched fraction/extracts (PE) inhibit lipopolysaccharide-induced atherosclerosis pro-inflammatory responses.
Chu FJ, Jin XB, Zhu JY.
Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China.
Abstract
AIM: To investigate the effects of housefly maggot (Musca domestica) protein-enriched fraction/extracts (PE) on lipopolysaccharide (LPS)-induced atherosclerosis (AS) proinflammatory responses in mice and macrophages. METHODS: The mouse model of AS was established by feeding a cholesterol-enriched diet and inducing by LPS. Changes in the levels of blood lipids (total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL)) and pro-inflammatory cytokines (interferon-gamma (IFN), tumor necrosis factor alpha (TNF) and interleukin-1alpha (IL-1)) were determined. Histomorphometric analysis of the pathological condition of the artery was also carried out. The macrophages were stimulated by LPS in the presence or absence of PE, and then the levels of TNF, IL-1 and monocyte chemotactic protein 1 (MCP-1) in cell culture supernatant were measured. RESULTS: Compared with the negative control group, the levels of three proinflammatory cytokines were significantly enhanced in the PE treatment group (p< 0.01). The concentrations of TC, TG and LDL were lower in the PE treatment group than in the
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negative control group (p< 0.01). HDL concentration in the PE treatment group was higher than in the negative control group (p< 0.01). Histomorphometric analysis showed that the thickness of the intima and media area, as well as the area ratio of the intima to media in the PE treatment group were lower than in the negative control group (p< 0.01). The expression of TNF, IL-1 and MCP-1 in LPS-induced macrophages was inhibited by different concentrations of PE (p< 0.01). CONCLUSION: These results indicate that PE potently inhibited multiple pro-inflammatory responses in experimental atherosclerosis lesions in vivo, and possessed anti-proinflammatory properties in vitro.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals Atherosclerosis/chemically induced Atherosclerosis/drug therapy* Blood Vessels/pathology Cells, Cultured Cholesterol/administration & dosage Cytokines/blood Houseflies/chemistry* Inflammation/prevention & control* Insect Proteins/isolation & purification Insect Proteins/pharmacology Insect Proteins/therapeutic use* Larva/chemistry* Lipids/blood Lipopolysaccharides Macrophages/drug effects Mice Substances Cytokines Insect Proteins Lipids Lipopolysaccharides Cholesterol
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Sheng Li Xue Bao. 2010 Aug 25;62(4):333-8.
14.
[Sphingomyelin synthase 2 deficiency decreases atherosclerosis and inhibits inflammation in mice].

[Article in Chinese]
Qin R, Chen ML, Zhu K, Deng JB, Shi YY.
Institute of Neurobiology, Medical College of Henan University, Kaifeng, China.
Abstract
Plasma sphingomyelin (SM) has been shown to be an independent risk factor for coronary heart disease, and sphingomyelin synthase 2 (SMS2) contributes to de novo SM biosynthesis and plasma membrane SM levels. The aim of the present study is to evaluate the in vivo role of SMS2 deficiency in serum SM metabolism and atherosclerosis (AS) development. We used male SMS2 knockout (SMS2(-/-)) and C57BL/6J (wild-type, WT) mice as experimental and control groups, respectively. Each group was fed high-fat diet (1% cholesterol, 20% leaf fat), as well as bile salt for accelerating the atherosclerotic formation. After three months of feeding, the mice were killed to observe aortic arches and oil red-stained longitudinal sections of thoracoabdominal aortae. Fasting blood samples were taken from the tail vein before and after high-fat diet, and the serum lipid and SM levels were measured by using kits and enzymatic method respectively. Western blot was used to analyze the contents of nuclear factor-kappaB (NFkappaB) p65 subunit in peritoneal macrophages stimulated with lipopolysaccharide (LPS) after high-fat diet. The results showed that after high-fat diet, SMS2(-/-) mice presented decreased atherosclerotic lesions in aortic arch and thoracoabdominal aorta compared with WT mice. Regardless of whether high-fat diet were given or not, SMS2(-/-) mice showed a significant decrease in serum SM level (P<0.05), but no significant changes in serum lipid levels, compared with WT mice. The expressions of NFkappaB p65 were attenuated in macrophages from SMS2(-/-) mice in response to LPS stimulation compared with those of the WT mice. These results suggest that SMS2 deficiency decreases AS and inhibits inflammation in mice. Thus, SMS2 deficiency may be a potential therapeutic strategy.
PMID: 20717634 [PubMed - in process] Free full text
Publication Types
Publication Types English Abstract Research Support, Non-U.S. Gov't
J Lipid Res. 2010 Nov;51(11):3196-206. Epub 2010 Jul 21.
15.
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Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol.
Zhu X, Owen JS, Wilson MD, Li H, Griffiths GL, Thomas MJ, Hiltbold EM, Fessler MB, Parks JS.
Departments of Pathology/Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Abstract
We previously showed that macrophages from macrophage-specific ATP-binding cassette transporter A1 (ABCA1) knockout (Abca1(-M/-M)) mice had an enhanced proinflammatory response to the Toll-like receptor (TLR) 4 agonist, lipopolysaccharide (LPS), compared with wild-type (WT) mice. In the present study, we demonstrate a direct association between free cholesterol (FC), lipid raft content, and hyper-responsiveness of macrophages to LPS in WT mice. Abca1(-M/-M) macrophages were also hyperresponsive to specific agonists to TLR2, TLR7, and TLR9, but not TLR3, compared with WT macrophages. We hypothesized that ABCA1 regulates macrophage responsiveness to TLR agonists by modulation of lipid raft cholesterol and TLR mobilization to lipid rafts. We demonstrated that Abca1(-M/-M) vs. WT macrophages contained 23% more FC in isolated lipid rafts. Further, mass spectrometric analysis suggested raft phospholipid composition was unchanged. Although cell surface expression of TLR4 was similar between Abca1(-M/-M) and WT macrophages, significantly more TLR4 was distributed in membrane lipid rafts in Abca1(-M/-M) macrophages. Abca1(-M/-M) macrophages also exhibited increased trafficking of the predominantly intracellular TLR9 into lipid rafts in response to TLR9-specific agonist (CpG). Collectively, our data suggest that macrophage ABCA1 dampens inflammation by reducing MyD88-dependent TLRs trafficking to lipid rafts by selective reduction of FC content in lipid rafts.

Publication Types Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't MeSH Terms ATP-Binding Cassette Transporters/genetics ATP-Binding Cassette Transporters/metabolism* Animals Cholesterol/metabolism* Gene Deletion Inflammation/metabolism
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Lipopolysaccharides/pharmacology Macrophages/cytology Macrophages/drug effects Macrophages/metabolism* Membrane Microdomains/drug effects Membrane Microdomains/metabolism* Mice Mice, Inbred C57BL Myeloid Differentiation Factor 88/metabolism* NF-kappa B/metabolism Protein Transport/drug effects Signal Transduction/drug effects Toll-Like Receptor 4/agonists Toll-Like Receptor 4/metabolism Toll-Like Receptor 9/agonists Toll-Like Receptor 9/metabolism Toll-Like Receptors/agonists Toll-Like Receptors/metabolism* Substances ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Lipopolysaccharides Myeloid Differentiation Factor 88 NF-kappa B Toll-Like Receptor 4 Toll-Like Receptor 9 Toll-Like Receptors Cholesterol Grant Support AT-27820/AT/NCCAM NIH HHS/United States HL-094525/HL/NHLBI NIH HHS/United States HL-49373/HL/NHLBI NIH HHS/United States R01 HL094525-03/HL/NHLBI NIH HHS/United States R01 HL094525-04/HL/NHLBI NIH HHS/United States Z01 ES102005/ES/NIEHS NIH HHS/United States
Mol Med. 2010 Sep-Oct;16(9-10):438-49. Epub 2010 May 12.
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ATP-binding membrane cassette transporter A1 (ABCA1): a possible link between inflammation and reverse cholesterol transport.
Yin K, Liao DF, Tang CK.
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, China.
Abstract
Atherosclerosis is characterized by a chronic inflammatory condition that involves numerous cellular and molecular inflammatory components. A wide array of inflammatory mediators, such as cytokines and proteins produced by macrophages and other cells, play a critical role in the development and progression of the disease. ATP-binding membrane cassette transporter A1 (ABCA1) is crucial for cellular cholesterol efflux and reverse cholesterol transport (RCT) and is also identified as an important target in antiatherosclerosis treatment. Evidence from several recent studies indicates that inflammation, along with other atherogenic-related mediators, plays distinct regulating roles in ABCA1 expression. Proatherogenic cytokines such as interferon (IFN)- and interleukin (IL)-1 have been shown to inhibit the expression of ABCA1, while antiatherogenic cytokines, including IL-10 and transforming growth factor (TGF)-1, have been shown to promote the expression of ABCA1. Moreover, some cytokines such as tumor necrosis factor (TNF)- seem to regulate ABCA1 expression in species-specific and dose-dependent manners. Inflammatory proteins such as C-reactive protein (CRP) and cyclooxygenase (COX)-2 are likely to inhibit ABCA1 expression during inflammation, and inflammation induced by lipopolysaccharide (LPS) was also found to block the expression of ABCA1. Interestingly, recent experiments revealed ABCA1 can function as an antiinflammatory receptor to suppress the expression of inflammatory factors, suggesting that ABCA1 may be the molecular basis for the interaction between inflammation and RCT. This review aims to summarize recent findings on the role of inflammatory cytokines, inflammatory proteins, inflammatory lipids, and the endotoxinmediated inflammatory process in expression of ABCA1. Also covered is the current understanding of the function of ABCA1 in modulating the immune response and inflammation through its direct and indirect antiinflammatory mechanisms including lipid transport, high-density lipoprotein (HDL) formation and apoptosis.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms ATP-Binding Cassette Transporters/metabolism*
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Animals Biological Transport Cholesterol/metabolism* Cytokines/metabolism Humans Immunity Inflammation/immunology Inflammation/metabolism* Substances ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Cytokines Cholesterol
Am J Respir Crit Care Med. 2010 Aug 1;182(3):404-12. Epub 2010 Apr 15.
17.
ATP-binding cassette transporter G1 deficiency dysregulates host defense in the lung.

Draper DW, Madenspacher JH, Dixon D, King DH, Remaley AT, Fessler MB.
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Abstract
RATIONALE: Mice with genetic deletion of the cholesterol efflux transporter, ATPbinding cassette (ABC) G1, have pulmonary lipidosis and chronic pulmonary inflammation. Whether ABCG1 regulates host defense is unknown. OBJECTIVES: To determine whether ABCG1 regulates pulmonary innate immunity and host defense, and to investigate the underlying molecular/cellular mechanisms. Methods: Abcg1(+/+) and Abcg1(-/-) mice were challenged with intrapulmonary lipopolysaccharide (LPS) or Klebsiella pneumoniae, intravenous K. pneumoniae, or intraperitoneal LPS. Phenotypic responses were profiled. Bone marrow chimeras and in vitro assays were used to differentiate and characterize the role of hematopoietic versus nonhematopoietic ABCG1 in host defense. MEASUREMENTS AND MAIN RESULTS: Unexposed Abcg1(-/-) mice had normal numbers of circulating neutrophils, but increased neutrophil recruitment to the airspace and lung parenchyma, and increased airspace cytokines and chemokines in the steady state. After intrapulmonary LPS or K. pneumoniae, Abcg1(-/-) mice displayed exaggerated further neutrophil recruitment to and degranulation in the airspace, and elevated airspace cytokine/chemokine induction. Alveolar macrophage ABCG1 was critical, as ABCG1 deficiency in hematopoietic cells was sufficient to enhance responses in vivo, and Abcg1(/-) alveolar macrophages adopted a "foam cell" phenotype, and were hyperresponsive ex vivo. Pulmonary compartmentalization and clearance of K. pneumoniae were increased in
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Abcg1(-/-) mice, indicating enhanced host defense. By contrast, Abcg1(+/+) and Abcg1(-/) mice had equivalent responses to intravenous K. pneumoniae and intraperitoneal LPS, suggesting that ABCG1 regulates innate immunity in a tissue-selective manner. CONCLUSIONS: Abcg1(-/-) mice have an enhanced pulmonary host defense response driven predominantly by hematopoietic cells.

Publication Types Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural MeSH Terms ATP-Binding Cassette Transporters/genetics ATP-Binding Cassette Transporters/physiology* Animals Bronchoalveolar Lavage Fluid/cytology Cytokines/metabolism Gene Deletion Immunity, Innate* Klebsiella pneumoniae Leukocyte Count Leukocytes/metabolism Lipopolysaccharides/administration & dosage Lipoproteins/genetics Lipoproteins/physiology* Lung/immunology* Lung/metabolism Macrophages/metabolism Macrophages/pathology Mice Mice, Inbred C57BL Neutrophil Activation Neutrophils/metabolism Substances ABCG1 protein, mouse ATP-Binding Cassette Transporters Cytokines
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Lipopolysaccharides Lipoproteins Grant Support Z01 ES102005/ES/NIEHS NIH HHS/United States
J Immunol. 2010 May 1;184(9):4810-8. Epub 2010 Mar 24.
18.
CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages.

Gleissner CA, Shaked I, Little KM, Ley K.
Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Abstract
In atherosclerotic arteries, blood monocytes differentiate to macrophages in the presence of growth factors, such as macrophage colony-stimulation factor (M-CSF), and chemokines, such as platelet factor 4 (CXCL4). To compare the gene expression signature of CXCL4-induced macrophages with M-CSF-induced macrophages or macrophages polarized with IFN-gamma/LPS (M1) or IL-4 (M2), we cultured primary human peripheral blood monocytes for 6 d. mRNA expression was measured by Affymetrix gene chips, and differences were analyzed by local pooled error test, profile of complex functionality, and gene set enrichment analysis. Three hundred seventy-five genes were differentially expressed between M-CSF- and CXCL4-induced macrophages; 206 of them overexpressed in CXCL4 macrophages coding for genes implicated in the inflammatory/immune response, Ag processing and presentation, and lipid metabolism. CXCL4-induced macrophages overexpressed some M1 and M2 genes and the corresponding cytokines at the protein level; however, their transcriptome clustered with neither M1 nor M2 transcriptomes. They almost completely lost the ability to phagocytose zymosan beads. Genes linked to atherosclerosis were not consistently upregulated or downregulated. Scavenger receptors showed lower and cholesterol efflux transporters showed higher expression in CXCL4- than M-CSF-induced macrophages, resulting in lower low-density lipoprotein content. We conclude that CXCL4 induces a unique macrophage transcriptome distinct from known macrophage types, defining a new macrophage differentiation that we propose to call M4.

Publication Types Comparative Study Research Support, Non-U.S. Gov't
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MeSH Terms Atherosclerosis/genetics Atherosclerosis/immunology Atherosclerosis/pathology Biological Markers/blood Cell Differentiation/genetics Cell Differentiation/immunology* Cell Lineage/genetics Cell Lineage/immunology Cell Polarity/genetics Cell Polarity/immunology Cells, Cultured Disease Progression Gene Expression Profiling* Humans Macrophage Colony-Stimulating Factor/blood Macrophage Colony-Stimulating Factor/physiology Macrophages/cytology Macrophages/immunology* Macrophages/metabolism* Monocytes/cytology Monocytes/immunology* Monocytes/metabolism* Platelet Factor 4/blood Platelet Factor 4/physiology* Substances Biological Markers Platelet Factor 4 Macrophage Colony-Stimulating Factor Grant Support R01 HL058108/HL/NHLBI NIH HHS/United States
Am J Physiol Cell Physiol. 2010 Jun;298(6):C1538-48. Epub 2010 Mar 10.
19.
Apolipoprotein A-I mimetic 4F alters the function of human monocyte-derived macrophages.

Smythies LE, White CR, Maheshwari A, Palgunachari MN, Anantharamaiah GM, Chaddha M, Kurundkar AR, Datta G.
University of Alabama, Birmingham, AL 35294, USA.
14-10-2012
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Abstract
HDL and its major protein component apolipoprotein A-I (apoA-I) exert anti-inflammatory effects, inhibit monocyte chemotaxis/adhesion, and reduce vascular macrophage content in inflammatory conditions. In this study, we tested the hypothesis that the apoA-I mimetic 4F modulates the function of monocyte-derived macrophages (MDMs) by regulating the expression of key cell surface receptors on MDMs. Primary human monocytes and THP-1 cells were treated with 4F, apoA-I, or vehicle for 7 days and analyzed for expression of cell surface markers, adhesion to human endothelial cells, phagocytic function, cholesterol efflux capacity, and lipid raft organization. 4F and apoA-I treatment decreased the expression of HLA-DR, CD86, CD11b, CD11c, CD14, and Toll-like receptor -4 (TLR-4) compared with control cells, suggesting the induction of monocyte differentiation. Both treatments abolished LPS-induced mRNA for monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 (MIP-1), regulated on activation, normal T-expressed and presumably secreted (RANTES), IL-6, and TNF-alpha but significantly upregulated LPS-induced IL-10 expression. Moreover, 4F and apoA-I induced a 90% reduction in the expression of CD49d, a ligand for the VCAM-1 receptor, with a concurrent decrease in monocyte adhesion (55% reduction) to human endothelial cells and transendothelial migration (34 and 27% for 4F and apoA-I treatments) compared with vehicle treatment. In addition, phagocytosis of dextran-FITC beads was inhibited by 4F and apoA-I, a response associated with reduced expression of CD32. Finally, 4F and apoA-I stimulated cholesterol efflux from MDMs, leading to cholesterol depletion and disruption of lipid rafts. These data provide evidence that 4F, similar to apoA-I, induces profound functional changes in MDMs, possibly due to differentiation to an antiinflammatory phenotype.

Publication Types Research Support, N.I.H., Extramural MeSH Terms Anti-Inflammatory Agents/pharmacology* Antigens, CD/metabolism Apolipoprotein A-I/pharmacology* Cell Adhesion/drug effects Cell Adhesion Molecules/metabolism Cells, Cultured Cholesterol/metabolism Cytokines/genetics Cytokines/metabolism
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Endothelial Cells/drug effects Endothelial Cells/immunology Endothelial Cells/metabolism HLA-DR Antigens/metabolism Humans Inflammation Mediators/metabolism Leukocyte Rolling/drug effects Lipopolysaccharides/pharmacology Macrophages/drug effects* Macrophages/immunology Macrophages/metabolism Membrane Microdomains/drug effects Membrane Microdomains/metabolism Molecular Mimicry Phagocytosis/drug effects Phenotype RNA, Messenger/metabolism Substances Anti-Inflammatory Agents Antigens, CD Apolipoprotein A-I Cell Adhesion Molecules Cytokines D-4F peptide HLA-DR Antigens Inflammation Mediators Lipopolysaccharides RNA, Messenger Cholesterol Grant Support AJ-1083539/PHS HHS/United States DK-064400/DK/NIDDK NIH HHS/United States DK-070040/DK/NIDDK NIH HHS/United States DK-074033/DK/NIDDK NIH HHS/United States GM082952/GM/NIGMS NIH HHS/United States HD-059142/HD/NICHD NIH HHS/United States HL-34343/HL/NHLBI NIH HHS/United States RR-020136/RR/NCRR NIH HHS/United States
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20. Am J Physiol Endocrinol Metab. 2010 May;298(5):E1036-48. Epub 2010 Feb 16.
A new antidiabetic compound attenuates inflammation and insulin resistance in Zucker diabetic fatty rats.
Lu M, Patsouris D, Li P, Flores-Riveros J, Frincke JM, Watkins S, Schenk S, Olefsky JM.
Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0673, USA.
Abstract
Tissue macrophage inflammatory pathways contribute to obesity-associated insulin resistance. Here, we have examined the efficacy and mechanisms of action of a novel anti -inflammatory compound (HE3286) in vitro and in vivo. In primary murine macrophages, HE3286 attenuates LPS- and TNFalpha-stimulated inflammation. In Zucker diabetic fatty rats, inflammatory cytokine/chemokine expression was downregulated in liver and adipose tissue by HE3286 treatment, as was macrophage infiltration into adipose tissue. In line with reduced inflammation, HE3286 treatment normalized fasting and fed glucose levels, improved glucose tolerance, and enhanced skeletal muscle and liver insulin sensitivity, as assessed by hyperinsulinemic euglycemic clamp studies. In phase 2 clinical trials, HE3286 treatment led to an enhancement in insulin sensitivity in humans. Gluconeogenic capacity was also reduced by HE3286 treatment, as evidenced by a reduced glycemic response during pyruvate tolerance tests and decreased basal hepatic glucose production (HGP) rates. Since serum levels of gluconeogenic substrates were decreased by HE3286, it indicates that the reduction of both intrinsic gluconeogenic capacity and substrate availability contributes to the decrease in HGP. Lipidomic analysis revealed that HE3286 treatment reduced liver cholesterol and triglyceride content, leading to a feedback elevation of LDL receptor and HMG-CoA reductase expression. Accordingly, HE3286 treatment markedly decreased total serum cholesterol. In conclusion, HE3286 is a novel anti-inflammatory compound, which displays both glucose-lowering and cholesterollowering effects.

Publication Types Clinical Trial, Phase II Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't MeSH Terms Adult Analysis of Variance Animals Blood Glucose/metabolism
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Blotting, Western Cell Movement/drug effects Chemokines/metabolism Cytokines/metabolism Dehydroepiandrosterone/analogs & derivatives* Dehydroepiandrosterone/pharmacology Female Gene Expression Gluconeogenesis/drug effects Glucose Clamp Technique Glucose Tolerance Test Humans Immunohistochemistry Inflammation/drug therapy* Inflammation/metabolism Insulin Resistance* Lipids/blood Lipopolysaccharides Liver/drug effects* Liver/metabolism Macrophages/drug effects* Macrophages/metabolism Male Mice Middle Aged Muscle, Skeletal/drug effects Muscle, Skeletal/metabolism Obesity/drug therapy* Obesity/metabolism Rats Rats, Zucker Substances 17-ethynyl-5-androstene-3, 7, 17-triol Blood Glucose Chemokines Cytokines Lipids Lipopolysaccharides Dehydroepiandrosterone Grant Support
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DK-033651/DK/NIDDK NIH HHS/United States DK-063491/DK/NIDDK NIH HHS/United States R01 DK033651-29/DK/NIDDK NIH HHS/United States U54-HD-012303-25/HD/NICHD NIH HHS/United States
J Biol Chem. 2010 Apr 2;285(14):10273-80. Epub 2010 Feb 9.
21.
Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1.
Hui X, Li H, Zhou Z, Lam KS, Xiao Y, Wu D, Ding K, Wang Y, Vanhoutte PM, Xu A.
Department of Medicine, Research Center of Heart, Brain, Hormone, and Healthy Aging, University of Hong Kong, Hong Kong.
Abstract
Adipocyte fatty acid-binding protein (A-FABP) has emerged as an important mediator of inflammation in macrophages. Macrophage-selective ablation of A-FABP alone is sufficient to prevent the development of high cholesterol diet-induced atherosclerosis in apoE-deficient mice. However, the precise mechanisms whereby A-FABP modulates inflammation remain elusive. Here, we report that A-FABP forms a finely tuned positive loop between JNK and activator protein-1 (AP-1) to exacerbate lipopolysaccharide (LPS)induced inflammatory responses in macrophages. Real time PCR and luciferase reporter analysis showed that LPS induced A-FABP expression through transcriptional activation. This effect was mediated by JNK, which promoted the recruitment of c-Jun to a highly conserved AP-1 consensus binding motif located within the proximal region of the A-FABP promoter. LPS-induced transactivation of the A-FABP gene was diminished by either pharmacological inhibition of JNK or knocking down c-Jun or by mutating the AP-1 recognition site within the proximal region (-122 to -116 bp) of the A-FABP promoter. Conversely, the LPS-evoked phosphorylation of JNK, activation of AP-1, and production of pro-inflammatory cytokines were markedly attenuated by pharmacological or genetic suppression of A-FABP in macrophages. Furthermore, the LPS-induced elevation in AFABP expression could also be prevented by the selective A-FABP inhibitor BMS309403. These findings support the notion that pharmacological inhibition of A-FABP represents a valid strategy for treating inflammation-related disorders such as atherosclerosis.

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MeSH Terms Adipocytes/metabolism Animals Base Sequence Blotting, Western Cells, Cultured Chromatin Immunoprecipitation Cytokines/metabolism Fatty Acid-Binding Proteins/physiology* Feedback, Physiological Inflammation/immunology Inflammation/metabolism* JNK Mitogen-Activated Protein Kinases/genetics JNK Mitogen-Activated Protein Kinases/metabolism* Lipopolysaccharides/pharmacology Luciferases/metabolism Macrophages/metabolism* Mice Molecular Sequence Data Phosphorylation Promoter Regions, Genetic/genetics RNA, Messenger/genetics RNA, Messenger/metabolism Reverse Transcriptase Polymerase Chain Reaction Sequence Homology, Nucleic Acid Transcription Factor AP-1/genetics Transcription Factor AP-1/metabolism* Substances Cytokines Fatty Acid-Binding Proteins Lipopolysaccharides RNA, Messenger Transcription Factor AP-1 Luciferases JNK Mitogen-Activated Protein Kinases
J Immunol. 2009 Nov 1;183(9):5917-27. Epub 2009 Oct 7.
22.
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Sodium benzoate, a metabolite of cinnamon and a food additive, reduces microglial and astroglial inflammatory responses.
Brahmachari S, Jana A, Pahan K.
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Abstract
Upon activation, microglia and astrocytes produce a number of proinflammatory molecules that participate in the pathophysiology of several neurodegenerative disorders. This study explores the anti-inflammatory property of cinnamon metabolite sodium benzoate (NaB) in microglia and astrocytes. NaB, but not sodium formate, was found to inhibit LPS-induced expression of inducible NO synthase (iNOS), proinflammatory cytokines (TNF-alpha and IL-1beta) and surface markers (CD11b, CD11c, and CD68) in mouse microglia. Similarly, NaB also inhibited fibrillar amyloid beta (Abeta)-, prion peptide-, double-stranded RNA (polyinosinic-polycytidylic acid)-, HIV-1 Tat-, 1-methyl-4-phenylpyridinium(+)-, IL-1beta-, and IL-12 p40(2)-induced microglial expression of iNOS. In addition to microglia, NaB also suppressed the expression of iNOS in mouse peritoneal macrophages and primary human astrocytes. Inhibition of NF-kappaB activation by NaB suggests that NaB exerts its anti-inflammatory effect through the inhibition of NF-kappaB. Although NaB reduced the level of cholesterol in vivo in mice, reversal of the inhibitory effect of NaB on iNOS expression, and NF-kappaB activation by hydroxymethylglutaryl-CoA, mevalonate, and farnesyl pyrophosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the antiinflammatory effect of NaB. Furthermore, we demonstrate that an inhibitor of p21(ras) farnesyl protein transferase suppressed the expression of iNOS, that activation of p21(ras) alone was sufficient to induce the expression of iNOS, and that NaB suppressed the activation of p21(ras) in microglia. These results highlight a novel anti-inflammatory role of NaB via modulation of the mevalonate pathway and p21(ras).

Publication Types Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't MeSH Terms Animals Astrocytes/drug effects Astrocytes/enzymology Astrocytes/pathology* CHO Cells
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Cells, Cultured Cinnamomum zeylanicum/metabolism* Cricetinae Cricetulus Cytokines/biosynthesis Food Additives/metabolism Food Additives/pharmacology* Humans Inflammation Mediators/antagonists & inhibitors* Inflammation Mediators/pharmacology Inflammation Mediators/physiology* Lipopolysaccharides/antagonists & inhibitors Lipopolysaccharides/pharmacology Mevalonic Acid/metabolism Mice Microglia/drug effects Microglia/enzymology Microglia/pathology* Nitric Oxide Synthase Type II/antagonists & inhibitors Nitric Oxide Synthase Type II/biosynthesis Sodium Benzoate/metabolism Sodium Benzoate/pharmacology* Substances Cytokines Food Additives Inflammation Mediators Lipopolysaccharides Mevalonic Acid Sodium Benzoate Nitric Oxide Synthase Type II Grant Support NS39940/NS/NINDS NIH HHS/United States R01 NS039940-10/NS/NINDS NIH HHS/United States
J Leukoc Biol. 2009 Nov;86(5):1227-38. Epub 2009 Aug 12.
23.
Cholesterol-dependent cytolysins induce rapid release of mature IL-1beta from murine macrophages in a NLRP3 inflammasome and cathepsin B-dependent manner.
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Chu J, Thomas LM, Watkins SC, Franchi L, Nez G, Salter RD.

Immunology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Abstract
CDC are exotoxins secreted by many Gram-positive bacteria that bind cholesterol and oligomerize to form pores in eukaryotic cell membranes. We demonstrate that CDC TLO induces caspase-1 cleavage and the rapid release of IL-1beta from LPS-primed murine BMDM. IL-1beta secretion depends on functional toxin pore formation, as free cholesterol, which prevents TLO binding to cell membranes, blocks the cytokine release. Secretion of the mature forms of IL-1beta and caspase-1 occurs only at lower TLO doses, whereas at a higher concentration, cells release the biologically inactive proforms. IL1beta release at a low TLO dose requires potassium efflux, calcium influx, and the activities of calcium-independent PLA(2), caspase-1, and cathepsin B. Additionally, mature IL-1beta release induced by a low TLO dose is dependent on the NLRP3 inflammasome, and pro-IL-1beta release induced by a high TLO dose occurs independently of NLRP3. These results further elucidate a mechanism of CDC-induced IL1beta release and suggest a novel, immune evasion strategy in which IL-1beta-containing macrophages might release primarily inactive cytokine following exposure to high doses of these toxins.

Publication Types Research Support, N.I.H., Extramural MeSH Terms Animals Carrier Proteins/physiology* Cathepsin B/physiology* Cholesterol/pharmacology* Cytotoxins/pharmacology* Cytotoxins/toxicity Enzyme-Linked Immunosorbent Assay Exotoxins/toxicity* Flow Cytometry Gram-Positive Bacteria/physiology Inflammation/blood Inflammation/physiopathology Interleukin-1beta/secretion* Lipopolysaccharides/pharmacology Macrophages/cytology
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Macrophages/drug effects Macrophages/secretion* Mice Pepstatins/pharmacology Substances CIAS1 protein, mouse Carrier Proteins Cytotoxins Exotoxins Interleukin-1beta Lipopolysaccharides Pepstatins pepstatin Cholesterol Cathepsin B Grant Support AI063331/AI/NIAID NIH HHS/United States AI064748/AI/NIAID NIH HHS/United States AI57168/AI/NIAID NIH HHS/United States CA082084/CA/NCI NIH HHS/United States CA73743/CA/NCI NIH HHS/United States
Atherosclerosis. 2010 Jan;208(1):134-41. Epub 2009 Jul 15.
24.
Anti-inflammatory and recycling properties of an apolipoprotein mimetic peptide, Ac-hE18A-NH(2).

Datta G, White CR, Dashti N, Chaddha M, Palgunachari MN, Gupta H, Handattu SP, Garber DW, Anantharamaiah GM.
Department of Medicine, Atherosclerosis Research Unit, Division of Gerontology, Geriatrics and Palliative Medicine, University of Alabama at Birmingham, 1808 Seventh Avenue South, Birmingham, AL 35294, USA. gdatta@uab.edu
Abstract
Apolipoprotein E (apoE) exerts prominent anti-inflammatory effects and undergoes recycling by target cells. We previously reported that the peptide Ac-hE18A-NH(2), composed of the receptor binding domain (LRKLRKRLLR) of apoE covalently linked to the Class A amphipathic peptide 18A, dramatically lowers plasma cholesterol and lipid hydroperoxides and enhances paraoxonase activity in dyslipidemic animal models. The objective of this study was to determine whether this peptide, analogous to apoE, exerts anti-inflammatory effects and undergoes recycling under in vitro conditions. Pulse chase studies using [(125)I]-Ac-hE18A-NH(2) in THP-1 derived macrophages and HepG2 cells
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showed greater amounts of intact peptide in the cells at later time points indicating recycling of the peptide. Ac-hE18A-NH(2) induced a 2.5-fold increase in prebeta-HDL in the conditioned media of HepG2 cells. This effect persisted for 3 days after removal of the peptide from culture medium. Ac-hE18A-NH(2) also induced the secretion of cell surface apoE from THP-1 macrophages. In addition, the peptide increased cholesterol efflux from THP-1 cells by an ABCA1 independent mechanism. Moreover, Ac-hE18A-NH(2) inhibited LPS-induced vascular cell adhesion molecule-1 (VCAM-1) expression, and reduced monocyte adhesion in human umbilical vein endothelial cells (HUVECs). It also reduced the secretion of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) from THP-1 macrophages even when administered post-LPS and abolished the 18-fold increase in LPS-induced mRNA levels for MCP-1 in THP-1 cells. Taken together, these results suggest that addition of the putative apoE receptor-domain to the Class A amphipathic peptide 18A results in a peptide that, similar to apoE, recycles, thus enabling the potentiation and prolongation of its anti-atherogenic and anti-inflammatory effects. Such a peptide has great potential as a therapeutic agent in the management of atherosclerosis and other inflammatory diseases. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.

Publication Types Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't MeSH Terms Animals Anti-Inflammatory Agents/pharmacology* Cells, Cultured High-Density Lipoproteins, Pre-beta/biosynthesis High-Density Lipoproteins, Pre-beta/drug effects Humans Inflammation/prevention & control Lipoproteins/pharmacology* Peptide Fragments/pharmacology* Peptides/metabolism Rabbits Time Factors Substances Ac-hE18A-NH(2)
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Anti-Inflammatory Agents High-Density Lipoproteins, Pre-beta Lipoproteins Peptide Fragments Peptides Grant Support DK070040/DK/NIDDK NIH HHS/United States GM082952/GM/NIGMS NIH HHS/United States HL084685/HL/NHLBI NIH HHS/United States HL085282/HL/NHLBI NIH HHS/United States HL65663/HL/NHLBI NIH HHS/United States R01 GM082952-02/GM/NIGMS NIH HHS/United States
Inflamm Res. 2009 Nov;58(11):809-18. Epub 2009 Jun 17.
25.
Inflammatory stress increases unmodified LDL uptake via LDL receptor: an alternative pathway for macrophage foamcell formation.
Ye Q, Chen Y, Lei H, Liu Q, Moorhead JF, Varghese Z, Ruan XZ.
Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China. qiangye78@126.com
Abstract
OBJECTIVE: To investigate if inflammatory stress increases intracellular accumulation of unmodified low-density lipoprotein (LDL) in human monocyte cell line (THP-1) macrophages by disrupting the sterol regulatory element binding proteins (SREBPs) cleavage-activating protein (SCAP)-SREBP2-mediated feedback regulation of LDL receptor. MATERIALS AND METHODS: THP-1 macrophages were incubated in serum-free medium in the absence or presence of LDL alone, LDL plus lipopolysaccharide (LPS) and LPS alone, then intracellular cholesterol content, tumor necrosis factor alpha level in the supernatants, mRNA and protein expression of LDL receptor, and SREBP2 and SCAP in the treated cells were assessed by Oil Red O staining, cholesterol enzymatic assay, enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, and Western blotting analysis, respectively. RESULTS: We demonstrated that LPS enhanced transformation of THP-1 macrophages into foam cells by increased uptake of unmodified LDL as evidenced by Oil Red O staining and direct assay of intracellular cholesterol. In the absence of LPS, 25 microg/ml LDL decreased LDL receptor mRNA and protein expression (p < 0.05). However, LPS enhanced LDL receptor expression, overcoming the suppression of LDL receptor induced by 25 microg/ml LDL and inappropriately increasing LDL uptake (p < 0.05). Exposure to
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LPS also caused overexpression of mRNA and protein of SCAP and SREBP2 (p < 0.05). These observations indicate that LPS disrupts cholesterol-mediated LDL receptor feedback regulation, permitting intracellular accumulation of unmodified LDL and causing foam-cell formation. CONCLUSION: The implication of these findings is that inflammatory stress may contribute to intracellular LDL accumulation in THP-1 macrophages without previous modification of LDL.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals Cell Line Foam Cells/cytology Foam Cells/metabolism* Humans Inflammation/physiopathology* Intracellular Signaling Peptides and Proteins/metabolism Lipopolysaccharides/immunology Lipopolysaccharides/pharmacology Lipoproteins, LDL/metabolism* Macrophages/cytology Macrophages/drug effects Macrophages/physiology* Membrane Proteins/metabolism Receptors, LDL/genetics Receptors, LDL/metabolism* Sterol Regulatory Element Binding Protein 2/immunology Stress, Physiological* Tumor Necrosis Factor-alpha/immunology Substances Intracellular Signaling Peptides and Proteins Lipopolysaccharides Lipoproteins, LDL Membrane Proteins Receptors, LDL
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SREBF2 protein, human SREBP cleavage-activating protein Sterol Regulatory Element Binding Protein 2 Tumor Necrosis Factor-alpha
J Agric Food Chem. 2009 Mar 25;57(6):2588-94.
26.
Inhibitory effects of grape seed procyanidins on foam cell formation in vitro.

Terra X, Fernndez-Larrea J, Pujadas G, Ardvol A, Blad C, Salvad J, Arola L, Blay M.
Department of Biochemistry and Biotechnology, Unitat d'Enologia del Centre de Referencia en Tecnologia dels Aliments de la Generalitat de Catalunya, Universitat Rovira i Virgili, Tarragona, Spain.
Abstract
Human and animal studies have demonstrated that procyanidin-rich diets reduce the risk of cardiovascular diseases and atherosclerosis. Some beneficial effects have been attributed to the well-known antioxidant activity of procyanidins. This study investigated another potential corrective role of procyanidins in cholesterol flux and inflammation in macrophage-derived foam cells. RAW 264.7 macrophages were cultured with moderately oxidized LDL (oxLDL), minimally oxidized LDL (moxLDL), or LPS (0.5 microg/mL) and oxLDL (LPS + oxLDL) to induce foam cells. Then, cells were treated with procyanidins derived from grape seed (PE, 45 microg/mL) for the last 12 h of incubation with the different lipoproteins (25 microg/mL). After lipid extraction, it was determined that total and esterified cholesterol and triglyceride accumulations in foam cells were increased by lipoprotein treatment but reduced by PE incubation. To asses the effect of PE on gene expression, the relative mRNA levels of CD36, ABCA1, iNOS, COX-2, and IkappaBalpha were determined by RT-PCR. It was shown that PE reduced the oxLDL scavenger receptor expression (CD36) and enhanced ATP-binding cassette A1 (ABCA1) expression, a key regulator of macrophage cholesterol efflux. PE also down-regulated inflammatory-related genes such as inducible nitric oxide synthase (iNOS) and kappa beta inhibitor-alpha (IkappaBalpha) without modifying COX-2 expression. In conclusion, evidence is provided that procyanidins may attenuate the development of foam cell formation by reducing cholesterol accumulation and modulating the expression of key genes in cholesterol flux and inflammation.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms
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Animals Cell Line Cholesterol/genetics Cholesterol/metabolism Foam Cells/drug effects* Foam Cells/metabolism Gene Expression/drug effects Inflammation/prevention & control Lipoproteins, LDL/pharmacology Macrophages/drug effects Mice Proanthocyanidins/pharmacology* Seeds/chemistry* Triglycerides/metabolism Vitis/chemistry* Substances Lipoproteins, LDL Proanthocyanidins Triglycerides oxidized low density lipoprotein Cholesterol
J Leukoc Biol. 2009 Feb;85(2):278-88. Epub 2008 Nov 12.
27.
Colony-stimulating factor-1 (CSF-1) delivers a proatherogenic signal to human macrophages.

Irvine KM, Andrews MR, Fernandez-Rojo MA, Schroder K, Burns CJ, Su S, Wilks AF, Parton RG, Hume DA, Sweet MJ.
The University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland, Australia.
Abstract
M-CSF/CSF-1 supports the proliferation and differentiation of monocytes and macrophages. In mice, CSF-1 also promotes proinflammatory responses in vivo by regulating mature macrophage functions, but little is known about the acute effects of this growth factor on mature human macrophages. Here, we show that in contrast to its effects on mouse bone marrow-derived macrophages, CSF-1 did not induce expression of urokinase plasminogen activator mRNA, repress expression of apolipoprotein E mRNA, or prime LPS-induced TNF and IL-6 secretion in human monocyte-derived macrophages (HMDM) from several independent donors. Instead, we show by expression profiling that CSF-1 modulates the HMDM transcriptome to favor a proatherogenic environment. CSF-1 induced expression of the proatherogenic chemokines CXCL10/IFN-inducible protein 10,
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CCL2, and CCL7 but repressed expression of the antiatherogenic chemokine receptor CXCR4. CSF-1 also up-regulated genes encoding enzymes of the cholesterol biosynthetic pathway (HMGCR, MVD, IDI1, FDPS, SQLE, CYP51A1, EBP, NSDHL, DHCR7, and DHCR24), and expression of ABCG1, encoding a cholesterol efflux transporter, was repressed. Consistent with these effects, CSF-1 increased levels of free cholesterol in HMDM, and the selective CSF-1R kinase inhibitor GW2580 ablated this response. These data demonstrate that CSF-1 represents a further link between inflammation and cardiovascular disease and suggest two distinct mechanisms by which CSF-1, which is known to be present in atherosclerotic lesions, may contribute to plaque progression.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals Atherosclerosis/immunology* Autocrine Communication Bone Marrow Cells/cytology Chemokines/immunology Cholesterol/biosynthesis Down-Regulation Humans Lipid Metabolism Macrophage Colony-Stimulating Factor/immunology* Macrophages/enzymology Macrophages/immunology* Male Mice Monocytes/cytology Receptors, CXCR4/genetics Receptors, CXCR4/metabolism Substances Chemokines Receptors, CXCR4 Cholesterol Macrophage Colony-Stimulating Factor
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Arterioscler Thromb Vasc Biol. 2009 Jan;29(1):12-8. Epub 2008 Oct 9.
28.
Rimonabant, a selective cannabinoid CB1 receptor antagonist, inhibits atherosclerosis in LDL receptordeficient mice.
Dol-Gleizes F, Paumelle R, Visentin V, Mars AM, Desitter P, Hennuyer N, Gilde A, Staels B, Schaeffer P, Bono F.
Sanofi-Aventis Recherche & Dveloppement, Toulouse, France.
Abstract
OBJECTIVE: The objective of this study was to determine whether the potent selective cannabinoid receptor-1 antagonist rimonabant has antiatherosclerotic properties. METHODS AND RESULTS: Rimonabant (50 mg/kg/d in the diet) significantly reduced food intake (from 3.35+/-.04 to 2.80+/-0.03 g/d), weight gain (from 14.6+/-0.7 g to -0.6+/0.3 g), serum total cholesterol (from 8.39+/-0.54 to 5.32+/-0.18 g/L), and atherosclerotic lesion development in the aorta (from 1.7+/-0.22 to 0.21+/-0.037 mm(2)) and aortic sinus (from 101,000+/-7800 to 27,000+/-2900 microm(2)) of LDLR(-/-) mice fed a Western-type diet for 3 months. Rimonabant also reduced plasma levels of the proinflammatory cytokines MCP-1 and IL12 by 85% (P<0.05) and 76% (P<0.05), respectively. Pair-fed animals had reduced weight gain (6.2+/-0.6 g gain), but developed atherosclerotic lesions which were as large as those of untreated animals, showing that the antiatherosclerotic effect of rimonabant is not related to reduced food intake. Interestingly, rimonabant at a lower dose (30 mg/kg/d in the diet) reduced atherosclerosis development in the aortic sinus (from 121,000+/-20,000 to 62,000+/-11,000 microm(2), 49% reduction, P<0.05), without affecting serum total cholesterol (7.8+/-0.7 g/L versus 8.1+/-1.3 g/L in the control group). Rimonabant decreased lipopolysaccharide (LPS)- and IL1beta-induced proinflammatory gene expression in mouse peritoneal macrophages in vitro as well as thioglycollate-induced recruitment of macrophages in vivo (10 mg/kg, p.o. bolus). CONCLUSIONS: These results show that rimonabant has antiatherosclerotic effects in LDLR(-/-) mice. These effects are partly unrelated to serum cholesterol modulation and could be related to an antiinflammatory effect.
Comment in
Cannabinoid CB1 receptor antagonists for atherosclerosis and cardiometabolic disorders: new hopes, old concerns? [Arterioscler Thromb Vasc Biol. 2009]

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MeSH Terms Animals Atherosclerosis/prevention & control* Cannabinoids/antagonists & inhibitors* Chemokine CCL2/blood Cholesterol/blood Cytokines/blood Energy Intake/drug effects Female Inflammation/prevention & control Interleukin-12/blood Mice Mice, Knockout Piperidines/therapeutic use* Pyrazoles/therapeutic use* Receptor, Cannabinoid, CB1/antagonists & inhibitors* Receptors, LDL/deficiency* Substances Cannabinoids Ccl2 protein, mouse Chemokine CCL2 Cytokines Piperidines Pyrazoles Receptor, Cannabinoid, CB1 Receptors, LDL rimonabant Interleukin-12 Cholesterol
Arterioscler Thromb Vasc Biol. 2008 Nov;28(11):2009-15. Epub 2008 Sep 11.
29.
Effect of macrophage overexpression of murine liver X receptor-alpha (LXR-alpha) on atherosclerosis in LDLreceptor deficient mice.
Teupser D, Kretzschmar D, Tennert C, Burkhardt R, Wilfert W, Fengler D, Naumann R, Sippel AE, Thiery J.
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Leipzig, Leipzig, Germany. teupser@medizin.uni-leipzig.de
Abstract
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Background- The nuclear liver X receptor-alpha (LXR-alpha) has been implicated in the regulation of intracellular cholesterol homeostasis, inflammatory response, and atherosclerosis susceptibility. The aim of the present study was to test whether transgenic expression of LXR-alpha might affect these mechanisms and result in a reduction of atherosclerosis. METHODS AND RESULTS: We generated mice with macrophage overexpression of mouse LXR-alpha, evidenced by significantly elevated expression levels of LXR-target genes (ABCA1, ABCG1) in these cells. For atherosclerosis studies, mice were crossed onto the LDL-receptor deficient background. Plasma lipids and lipoproteins as well as liver triglycerides were not significantly different between transgenic animals and nontransgenic controls. However, lesion area at the brachiocephalic artery (BCA) was significantly reduced (-83%, P=0.02) in male LXR-alpha transgenic mice. This was associated with a significantly increased cholesterol efflux to acceptor-free media (+24%, P=0.002) and ApoA1 containing media (+20%, P<0.0001) as well as reduced lipopolysaccharide (LPS)-induced NO-release from macrophages of transgenic animals, providing a potential mechanism for the reduction of atherosclerosis. CONCLUSIONS: Our data show for the first time that transgenic overexpression of LXR-alpha in macrophages has significant antiatherogenic properties. We conclude that overexpression of LXR-alpha in macrophages might be useful as a therapeutic principle for the prevention of atherosclerosis.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms ATP-Binding Cassette Transporters/metabolism Animals Atherosclerosis/genetics Atherosclerosis/metabolism Atherosclerosis/pathology Atherosclerosis/prevention & control* Brachiocephalic Trunk/metabolism Brachiocephalic Trunk/pathology Cells, Cultured Cholesterol, Dietary/metabolism DNA-Binding Proteins/genetics DNA-Binding Proteins/metabolism* Disease Models, Animal Female Inflammation/genetics
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Inflammation/metabolism Inflammation/pathology Inflammation/prevention & control* Lipoproteins/metabolism Liver/metabolism* Macrophages/metabolism* Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Nitric Oxide/metabolism Orphan Nuclear Receptors RNA, Messenger/metabolism Receptors, Cytoplasmic and Nuclear/genetics Receptors, Cytoplasmic and Nuclear/metabolism* Receptors, LDL/deficiency Receptors, LDL/genetics Receptors, LDL/metabolism* Up-Regulation Substances ABCG1 protein, mouse ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Cholesterol, Dietary DNA-Binding Proteins Lipoproteins Orphan Nuclear Receptors RNA, Messenger Receptors, Cytoplasmic and Nuclear Receptors, LDL liver X receptor Nitric Oxide
J Biol Chem. 2008 Aug 22;283(34):22930-41. Epub 2008 Jun 14.
30.
Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages.
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Zhu X, Lee JY, Timmins JM, Brown JM, Boudyguina E, Mulya A, Gebre AK, Willingham MC, Hiltbold EM, Mishra N, Maeda N, Parks JS.
Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Abstract
Macrophage-specific Abca1 knock-out (Abca1(-)(M)(/-)(M)) mice were generated to determine the role of macrophage ABCA1 expression in plasma lipoprotein concentrations and the innate immune response of macrophages. Plasma lipid and lipoprotein concentrations in chow-fed Abca1(-)(M)(/-)(M) and wild-type (WT) mice were indistinguishable. Compared with WT macrophages, Abca1(-)(M)(/-)(M) macrophages had a >95% reduction in ABCA1 protein, failed to efflux lipid to apoA-I, and had a significant increase in free cholesterol (FC) and membrane lipid rafts without induction of endoplasmic reticulum stress. Lipopolysaccharide (LPS)-treated Abca1(-)(M)(/-)(M) macrophages exhibited enhanced expression of pro-inflammatory cytokines and increased activation of the NF-kappaB and MAPK pathways, which could be diminished by silencing MyD88 or by chemical inhibition of NF-kappaB or MAPK. In vivo LPS injection also resulted in a higher pro-inflammatory response in Abca1(-)(M)(/-)(M) mice compared with WT mice. Furthermore, cholesterol depletion of macrophages with methyl-betacyclodextrin normalized FC content between the two genotypes and their response to LPS; cholesterol repletion of macrophages resulted in increased cellular FC accumulation and enhanced cellular response to LPS. Our results suggest that macrophage ABCA1 expression may protect against atherosclerosis by facilitating the net removal of excess lipid from macrophages and dampening pro-inflammatory MyD88dependent signaling pathways by reduction of cell membrane FC and lipid raft content.

Publication Types Research Support, N.I.H., Extramural MeSH Terms ATP-Binding Cassette Transporters/genetics* ATP-Binding Cassette Transporters/physiology Animals Cholesterol/metabolism* Inflammation MAP Kinase Signaling System Macrophages/metabolism* Membrane Microdomains/metabolism Mice Mice, Inbred C57BL
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Mice, Knockout Models, Biological Myeloid Differentiation Factor 88/physiology NF-kappa B/metabolism Signal Transduction beta-Cyclodextrins/metabolism Substances ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Myd88 protein, mouse Myeloid Differentiation Factor 88 NF-kappa B beta-Cyclodextrins methyl-beta-cyclodextrin Cholesterol Grant Support AT27820/AT/NCCAM NIH HHS/United States HL07115/HL/NHLBI NIH HHS/United States HL49373/HL/NHLBI NIH HHS/United States HL54176/HL/NHLBI NIH HHS/United States R01 HL094525-04/HL/NHLBI NIH HHS/United States R37 HL042630-16/HL/NHLBI NIH HHS/United States R37 HL042630-17/HL/NHLBI NIH HHS/United States R37 HL042630-18/HL/NHLBI NIH HHS/United States R37 HL042630-19/HL/NHLBI NIH HHS/United States
Biochemistry (Mosc). 2008 Mar;73(3):296-304.
31.
Lipid synthesis in macrophages during inflammation in vivo: effect of agonists of peroxisome proliferator activated receptors alpha and gamma and of retinoid X receptors.
Posokhova EN, Khoshchenko OM, Chasovskikh MI, Pivovarova EN, Dushkin MI.
Institute of Internal Medicine, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, Russia.
Abstract
The effects of peroxisome proliferator activated receptors alpha and gamma (PPAR-alpha and PPAR-gamma) and retinoid X receptor (RXR) agonists upon synthesis and accumulation of lipids in murine C57Bl macrophages during inflammation induced by injection of zymosan and Escherichia coli lipopolysaccharide (LPS) have been studied. It
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is significant that intraperitoneal injection of zymosan (50 mg/kg) or LPS (0.1 mg/kg) in mice led to a dramatic increase of [14C]oleate incorporation into cholesteryl esters and triglycerides and [14C]acetate incorporation into cholesterol and fatty acids in peritoneal macrophages. Lipid synthesis reached its maximum rate 18-24 h after injection and was decreased 5-7 days later to control level after LPS injection or was still heightened after zymosan injection. In macrophages obtained in acute phase of inflammation (24 h), degradation of 125I-labeled native low density lipoprotein (NLDL) was 4-fold increased and degradation of 125I-labeled acetylated LDL (AcLDL) was 2-3-fold decreased. Addition of NLDL (50 microg/ml) or AcLDL (25 microg/ml) into the incubation medium of activated macrophages induced 9-14- and 1.25-fold increase of cholesteryl ester synthesis, respectively, compared with control. Addition of NLDL and AcLDL into the incubation medium completely inhibited cholesterol synthesis in control macrophages but had only slightly effect on cholesterol synthesis in activated macrophages. Injection of RXR, PPAR-alpha, or PPAR-gamma agonists--9-cis-retinoic acid (5 mg/kg), bezafibrate (10 mg/kg), or rosiglitazone (10 mg/kg), respectively--30 min before zymosan or LPS injection led to significant decrease of lipid synthesis. Ten hour preincubation of activated in vivo macrophages with the abovementioned agonists (5 microM) decreased cholesteryl ester synthesis induced by NLDL and AcLDL addition into the cell cultivation medium. The data suggest that RXR, PPAR-alpha, or PPAR-gamma agonists inhibited lipid synthesis and induction of cholesteryl ester synthesis in inflammatory macrophages caused by capture of native or modified LDL.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Acetic Acid/metabolism Animals Cholesterol/biosynthesis Cholesterol/chemistry Cholesterol Esters/biosynthesis Cholesterol Esters/chemistry Fatty Acids/biosynthesis Inflammation/chemically induced Inflammation/metabolism* Lipids/biosynthesis* Lipopolysaccharides/administration & dosage Lipoproteins, LDL/metabolism Macrophages, Peritoneal/drug effects Macrophages, Peritoneal/metabolism* Male
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Mice Mice, Inbred C57BL Oleic Acid/metabolism PPAR alpha/agonists PPAR gamma/agonists Peroxisome Proliferator-Activated Receptors/agonists* Retinoid X Receptors/agonists* Triglycerides/biosynthesis Triglycerides/chemistry Zymosan/administration & dosage Substances Cholesterol Esters Fatty Acids Lipids Lipopolysaccharides Lipoproteins, LDL PPAR alpha PPAR gamma Peroxisome Proliferator-Activated Receptors Retinoid X Receptors Triglycerides acetyl-LDL Oleic Acid Cholesterol Acetic Acid Zymosan
Shock. 2008 Nov;30(5):590-5.
32.
Human cholesteryl ester transfer protein expression enhances the mouse survival rate in an experimental systemic inflammation model: a novel role for CETP.
Cazita PM, Barbeiro DF, Moretti AI, Quinto EC, Soriano FG.
Lipids Lab (LIM 10), Faculty of Medical Sciences of University of So Paulo, So Paulo, Brazil. lipideq@usp.br
Abstract
Mice expressing human cholesteryl ester transfer protein (huCETP) are more resistant to Escherichia coli bacterial wall LPS because death rates 5 days after intraperitoneal inoculation of LPS were higher in wild-type than in huCETP+/+ mice, whereas all huCETP+/+ mice remained alive. After LPS inoculation, plasma concentrations of TNF-
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alpha and IL-6 increased less in huCETP+/+ than in wild-type mice. LPS in vitro elicited lower TNF-alpha production by CETP expressing than by wild-type macrophages. In addition, TNF-alpha production by RAW 264.7 murine macrophages increased on incubation with LPS but decreased in a dose-dependent manner when human CETP was added to the medium. Human CETP in vitro enhanced the LPS binding to plasma highdensity lipoprotein/low-density lipoprotein. The liver uptake of intravenous infused 14CLPS from Salmonella typhimurium was greater in huCETP+/+ than in wild-type mice. Present data indicate for the first time that CETP is an endogenous component involved in the first line of defense against an exacerbated production of proinflammatory mediators.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals Cells, Cultured Cholesterol Ester Transfer Proteins/genetics Cholesterol Ester Transfer Proteins/pharmacology Cholesterol Ester Transfer Proteins/physiology* Cytokines/metabolism Humans Inflammation/genetics* Inflammation/mortality* Interleukin-6/blood Lipopolysaccharides/metabolism Lipopolysaccharides/pharmacokinetics Lipopolysaccharides/pharmacology Liver/drug effects Liver/metabolism Macrophages/metabolism Mice Mice, Transgenic Salmonella typhimurium/metabolism Spleen/drug effects Spleen/metabolism Survival Rate Tumor Necrosis Factor-alpha/blood
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Substances Cholesterol Ester Transfer Proteins Cytokines Interleukin-6 Lipopolysaccharides Tumor Necrosis Factor-alpha
Immunol Lett. 2008 Mar 15;116(2):178-83. Epub 2008 Jan 24.
33.
LDL uptake by monocytes in response to inflammation is MAPK dependent but independent of tribbles protein expression.
Eder K, Guan H, Sung HY, Francis SE, Crossman DC, Kiss-Toth E.
Cardiovascular Research Unit, University of Sheffield, United Kingdom.
Abstract
Inflammatory activation of monocytes is a hallmark event in cardiovascular disease. Activated monocytes migrate into atherosclerotic lesions, differentiate into macrophages and ingest lipids to become foam cells. These, in turn, through interaction with other inflammatory cell types contribute to plaque instability and are thought to play a key role in the development of acute coronary syndromes. In the current manuscript we investigated whether inflammatory activation of monocyte THP-1 cells influences their ability to take-up chemically modified LDL. We have also studied whether tribbles proteins, which have been shown to regulate the activation of inflammatory signal processing networks, have a modulatory role in the uptake of modified LDL by monocyte. Here, we show that activation of THP-1 cells by LPS potentiates LDL uptake. The greatest effect of LPS was seen after 16 h, compared to acute stimulation. Specific MAPK pathways are involved in this potentiation. Inhibition of both the p38 and ERK pathways led to reduced LPS uptake, specifically in LPS stimulated cells. Expression of tribbles, regulators of MAPK signalling, was dynamically modulated by LPS activation. However, neither suppression of tribbles expression by transient transfection of specific siRNAs nor transient overexpression of these proteins led to changes in the capacity of THP-1 cells to take up modified LDL. Therefore, we conclude that LPS potentiation of LDL uptake of THP-1 cells is MAPK dependent but is not mediated by tribbles.

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Cell Cycle Proteins/biosynthesis Cell Cycle Proteins/genetics Cell Line, Tumor Cholesterol, LDL/metabolism* Down-Regulation Gene Expression Regulation*/drug effects Humans Inflammation/immunology Inflammation/pathology Intracellular Signaling Peptides and Proteins/deficiency Intracellular Signaling Peptides and Proteins/genetics* Lipopolysaccharides/pharmacology Mitogen-Activated Protein Kinases/metabolism* Monocytes/drug effects Monocytes/metabolism* Protein-Serine-Threonine Kinases/biosynthesis Protein-Serine-Threonine Kinases/deficiency Protein-Serine-Threonine Kinases/genetics Repressor Proteins/biosynthesis Repressor Proteins/genetics Substances Cell Cycle Proteins Cholesterol, LDL Intracellular Signaling Peptides and Proteins Lipopolysaccharides Repressor Proteins TRIB1 protein, human TRIB2 protein, human TRIB3 protein, human Protein-Serine-Threonine Kinases Mitogen-Activated Protein Kinases Grant Support pg/02/122/British Heart Foundation/United Kingdom pg/05/100/British Heart Foundation/United Kingdom
J Immunol. 2008 Mar 1;180(5):3305-12.
34.
Effects of liver X receptor agonist treatment on pulmonary inflammation and host defense.
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Smoak K, Madenspacher J, Jeyaseelan S, Williams B, Dixon D, Poch KR, Nick JA, Worthen GS, Fessler MB.
Laboratory of Respiratory Biology, Department of Health and Human Services, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Abstract
Liver X receptor (LXR) alpha and beta are members of the nuclear receptor superfamily of ligand-activated transcription factors. Best known for triggering "reverse cholesterol transport" gene programs upon their activation by endogenous oxysterols, LXRs have recently also been implicated in regulation of innate immunity. In this study, we define a role for LXRs in regulation of pulmonary inflammation and host defense and identify the lung and neutrophil as novel in vivo targets for pharmacologic LXR activation. LXR is expressed in murine alveolar macrophages, alveolar epithelial type II cells, and neutrophils. Treatment of mice with TO-901317, a synthetic LXR agonist, reduces influx of neutrophils to the lung triggered by inhaled LPS, intratracheal KC chemokine, and intratracheal Klebsiella pneumoniae and impairs pulmonary host defense against this bacterium. Pharmacologic LXR activation selectively modulates airspace cytokine expression induced by both LPS and K. pneumoniae. Moreover, we report for the first time that LXR activation impairs neutrophil motility and identify inhibition of chemokineinduced RhoA activation as a putative underlying mechanism. Taken together, these data define a novel role for LXR in lung pathophysiology and neutrophil biology and identify pharmacologic activation of LXR as a potential tool for modulation of innate immunity in the lung.

Publication Types Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't MeSH Terms Administration, Oral Animals Cell Line Cell Migration Inhibition/drug effects Cell Migration Inhibition/immunology DNA-Binding Proteins/agonists* DNA-Binding Proteins/biosynthesis DNA-Binding Proteins/genetics DNA-Binding Proteins/physiology
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Female Humans Hydrocarbons, Fluorinated/administration & dosage* Immunity, Innate/drug effects Inflammation Mediators/agonists* Inflammation Mediators/metabolism Inflammation Mediators/physiology Klebsiella Infections/immunology* Klebsiella Infections/metabolism Klebsiella Infections/pathology Lung/drug effects Lung/immunology* Lung/microbiology Lung/pathology* Macrophages, Alveolar/drug effects Macrophages, Alveolar/immunology Macrophages, Alveolar/microbiology Mice Mice, Inbred C57BL Neutrophils/drug effects Neutrophils/immunology Neutrophils/microbiology Orphan Nuclear Receptors Receptors, Cytoplasmic and Nuclear/agonists* Receptors, Cytoplasmic and Nuclear/biosynthesis Receptors, Cytoplasmic and Nuclear/genetics Receptors, Cytoplasmic and Nuclear/physiology Respiratory Mucosa/drug effects Respiratory Mucosa/immunology Respiratory Mucosa/microbiology Sulfonamides/administration & dosage* U937 Cells Substances DNA-Binding Proteins Hydrocarbons, Fluorinated Inflammation Mediators Orphan Nuclear Receptors Receptors, Cytoplasmic and Nuclear Sulfonamides TO-901317 liver X receptor
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Grant Support 5P01HL68743-04/HL/NHLBI NIH HHS/United States 5R01HL061407-08/HL/NHLBI NIH HHS/United States P01 HL068743-040002/HL/NHLBI NIH HHS/United States R01 HL061407-08/HL/NHLBI NIH HHS/United States Z01 ES102005-02/ES/NIEHS NIH HHS/United States Z99 ES999999/ES/NIEHS NIH HHS/United States
World J Gastroenterol. 2007 Dec 21;13(47):6385-95.
35.
Intestinal endotoxemia plays a central role in development of hepatopulmonary syndrome in a cirrhotic rat model induced by multiple pathogenic factors.
Zhang HY, Han de W, Su AR, Zhang LT, Zhao ZF, Ji JQ, Li BH, Ji C.
Department of Pathophysiology, Changzhi Medical College, 161 Jie Fang Dong Jie, Changzhi 046000, Shanxi Province, China. zhhy2001@hotmail.com
Abstract
AIM: To characterize the correlation between severity of hepatopulmonary syndrome (HPS) and degree of hepatic dysfunction, and to explore how intestinal endotoxemia (IETM) affects the development of HPS in cirrhotic rats. METHODS: Male Wister rats were fed with a diet containing maize flour, lard, cholesterol, and alcohol and injected subcutaneously with CCl(4) oil solution every two days for 8 wk to induce typical cirrhosis and development of HPS. The animals were also given a nitric oxide (NO) production inhibitor, N(omega)-nitro-L-arginine methyl ester (LNAME) intraperitoneally, and an iNOS inhibitor, aminoguanidine hydrochloride (AG) via gavage daily from the end of the 4th wk to the end of the 6th or 8th wk, or a HO-1 inhibitor, zinc protoporphyrin (ZnPP) intraperitoneally 12 h prior to killing. Blood, liver and lung tissues were sampled. RESULTS: Histological deterioration of the lung paralleled to that of the liver in the cirrhotic rats. The number of pulmonary capillaries was progressively increased from 6.1 +/- 1.1 (count/filed) at the 4th wk to 14.5 +/- 2.4 (count/filed) at the 8th wk in the cirrhotic rats. Increased pulmonary capillaries were associated with increased blood levels of lipopolysaccharide (LPS) (0.31 +/- 0.08 EU/mL vs control 0.09 +/- 0.03 EU/mL), alanine transferase (ALT, 219.1 +/- 17.4 U/L vs control 5.9 +/- 2.2 U/L) and portal vein pressure. Compared with normal control animals, the number of total cells in bronchoalveolar lavage fluid (BALF) of the cirrhotic rats at the 8th wk was not changed, but the number of macrophages and the ratio of macrophages to total cells were increased by nearly 2fold, protein expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) started to increase significantly at the 4th wk, and reached its peak at the 8th wk in the lung of cirrhotic rats. The increase of iNOS expression appeared to be quicker than that of eNOS. NO(2)(-)/NO(3)(-) was also increased, which was correlated to the increase of iNOS (r = 0.7699, P < 0.0001) and eNOS (r = 0.5829, P <
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0.002). mRNA expression of eNOS and iNOS was highly consistent with their protein expression. CONCLUSION: Progression and severity of HPS as indicated by both increased pulmonary capillaries and histological changes are closely associated with LPS levels and progression of hepatic dysfunction as indicated by increased levels of ALT and portal vein pressure. Intestinal endotoxemia plays a central role in the development of HPS in the cirrhotic rat model by inducing NO and/or CO.

Publication Types Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't MeSH Terms Alanine Transaminase/blood Animals Bronchoalveolar Lavage Fluid/cytology Capillaries/pathology Carboxyhemoglobin/metabolism Cytokines/blood Disease Progression Endotoxemia/complications* Endotoxemia/metabolism Endotoxemia/pathology Endotoxemia/physiopathology Enzyme Inhibitors/pharmacology Guanidines/pharmacology Heme Oxygenase (Decyclizing)/antagonists & inhibitors Heme Oxygenase (Decyclizing)/metabolism Hepatopulmonary Syndrome/etiology* Hepatopulmonary Syndrome/metabolism Hepatopulmonary Syndrome/pathology Hepatopulmonary Syndrome/physiopathology Intestinal Diseases/complications* Intestinal Diseases/metabolism Intestinal Diseases/pathology Intestinal Diseases/physiopathology Lipopolysaccharides/blood
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Liver/enzymology Liver/pathology* Liver/physiopathology Liver Cirrhosis, Experimental/complications* Liver Cirrhosis, Experimental/metabolism Liver Cirrhosis, Experimental/pathology Liver Cirrhosis, Experimental/physiopathology Lung/blood supply Lung/drug effects Lung/enzymology Lung/pathology* Lung/physiopathology Male Malondialdehyde/blood NG-Nitroarginine Methyl Ester/pharmacology Neovascularization, Pathologic/etiology Neovascularization, Pathologic/pathology Nitric Oxide/metabolism Nitric Oxide Synthase Type II/antagonists & inhibitors Nitric Oxide Synthase Type II/metabolism Nitric Oxide Synthase Type III Portal Pressure Protoporphyrins/pharmacology Rats Rats, Wistar Severity of Illness Index Time Factors Up-Regulation Substances Cytokines Enzyme Inhibitors Guanidines Lipopolysaccharides Protoporphyrins Nitric Oxide zinc protoporphyrin NG-Nitroarginine Methyl Ester Malondialdehyde pimagedine Carboxyhemoglobin Nitric Oxide Synthase Type II
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Nitric Oxide Synthase Type III Nos2 protein, rat Nos3 protein, rat Heme Oxygenase (Decyclizing) Hmox1 protein, rat Alanine Transaminase Grant Support R01 AA014428/AA/NIAAA NIH HHS/United States
Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):272-7. Epub 2007 Nov 21.
36.
Antiinflammatory and antiatherogenic effects of the NFkappaB inhibitor acetyl-11-keto-beta-boswellic acid in LPSchallenged ApoE-/- mice.
Cuaz-Prolin C, Billiet L, Baug E, Copin C, Scott-Algara D, Genze F, Bchele B, Syrovets T, Simmet T, Rouis M.
INSERM UR545, Institut Pasteur de Lille, 1 rue du Professeur Calmette, 59019 Lille, France.
Abstract
OBJECTIVE: In this article, we studied the effect of acetyl-11-keto-beta-boswellic acid (AKbetaBA), a natural inhibitor of the proinflammatory transcription factor NF-kappaB on the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE-/-) mice. METHODS AND RESULTS: Atherosclerotic lesions were induced by weekly LPS injection in apoE-/- mice. LPS alone increased atherosclerotic lesion size by approximately 100%, and treatment with AKbetaBA significantly reduced it by approximately 50%. Moreover, the activity of NF-kappaB was also reduced in the atherosclerotic plaques of LPS-injected apoE-/- mice treated with AKbetaBA. As a consequence, AKbetaBA treatment led to a significant downregulation of several NFkappaB-dependent genes such as MCP-1, MCP-3, IL-1alpha, MIP-2, VEGF, and TF. By contrast, AKbetaBA did not affect the plasma concentrations of triglycerides, total cholesterol, antioxidized LDL antibodies, and various subsets of lymphocyte-derived cytokines. Moreover, AKbetaBA potently inhibited the IkappaB kinase (IKK) activity immunoprecipitated from LPS-stimulated mouse macrophages and mononuclear cells leading to decreased phosphorylation of IkappaB alpha and inhibition of p65/NF-kappaB activation. Comparable AKbetaBA-mediated inhibition was also observed in LPSstimulated human macrophages. CONCLUSIONS: The inhibition of NF-kappaB activity by plant resins from species of the Boswellia family might represent an alternative for classical medicine treatments for chronic inflammatory diseases such as atherosclerosis.
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Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals Apolipoproteins E/genetics* Atherosclerosis/drug therapy* Atherosclerosis/genetics Boswellia Cells, Cultured Disease Models, Animal Inflammation/drug therapy Lipopolysaccharides/administration & dosage Lipopolysaccharides/immunology Mice Mice, Knockout NF-kappa B/antagonists & inhibitors* NF-kappa B/drug effects* Plant Extracts/pharmacology* Triterpenes/pharmacology* Substances Apolipoproteins E Lipopolysaccharides NF-kappa B Plant Extracts Triterpenes acetyl-11-ketoboswellic acid
Circulation. 2007 Nov 6;116(19):2173-81. Epub 2007 Oct 22.
37.
Apolipoprotein C-I is crucially involved in lipopolysaccharide-induced atherosclerosis development in apolipoprotein E-knockout mice.
Westerterp M, Berbe JF, Pires NM, van Mierlo GJ, Kleemann R, Romijn JA, Havekes LM, Rensen PC.
The Netherlands Organization for Applied Scientific Research-Quality of Life, Department of Biomedical Research, Gaubius Laboratory, Leiden, The Netherlands. M.Westerterp@lumc.nl
14-10-2012
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Abstract
BACKGROUND: Lipopolysaccharide (LPS), which is released from gram-negative bacteria on multiplication or lysis, aggravates atherosclerosis in humans and rodents by inducing inflammation via toll-like receptors. Because apolipoprotein C-I (apoCI) enhances the LPS-induced inflammatory response in macrophages in vitro and in mice, we investigated the effect of endogenous apoCI expression on LPS-induced atherosclerosis in mice. METHODS AND RESULTS: Twelve-week-old apoe-/- apoc1-/- and apoe-/- apoc1+/+ mice received weekly intraperitoneal injections of LPS (50 microg) or vehicle for a period of 10 weeks, and atherosclerosis development was assessed in the aortic root. LPS administration did not affect atherosclerotic lesion area in apoe-/- apoc1-/- mice but increased it in apoe-/- apoc1+/+ mice. In fact, apoCI expression increased the LPSinduced atherosclerotic lesion area by 60% (P<0.05), concomitant with an increase in LPS -induced plasma levels of fibrinogen and E-selectin. This indicated that apoCI increased the LPS-induced inflammatory state, both systemically (ie, fibrinogen) and at the level of the vessel wall (ie, E-selectin). In addition, both macrophage-derived apoCI and HDLassociated apoCI increased the LPS-induced tumor necrosis factor-alpha response by macrophages in vitro. CONCLUSIONS: We conclude that apoCI is crucially involved in LPS-induced atherosclerosis in apoe-/- mice, which mainly relates to an increased inflammatory response toward LPS. We anticipate that apoCI plasma levels contribute to accelerated atherosclerosis development in individuals who have chronic infection.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals Apolipoproteins C/genetics* Apolipoproteins C/metabolism* Atherosclerosis/genetics* Atherosclerosis/immunology* Atherosclerosis/pathology Biological Markers/blood Cells, Cultured Cholesterol, HDL/blood E-Selectin/blood Female
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Fibrinogen/metabolism Hypercholesterolemia/genetics Hypercholesterolemia/immunology Hypercholesterolemia/pathology Lipopolysaccharides/pharmacology Macrophages, Peritoneal/metabolism Macrophages, Peritoneal/pathology Male Mice Mice, Inbred C57BL Mice, Mutant Strains Monocytes/pathology T-Lymphocytes/pathology Tumor Necrosis Factor-alpha/metabolism Vasculitis/genetics Vasculitis/immunology Vasculitis/pathology Substances Apolipoproteins C Biological Markers Cholesterol, HDL E-Selectin Lipopolysaccharides Tumor Necrosis Factor-alpha Fibrinogen
Life Sci. 2007 Oct 27;81(19-20):1403-10. Epub 2007 Sep 29.
38.
Roquinimex-mediated protection effect on the development of chronic graft-versus-host disease in mice is associated with induction of Th1 cytokine production and inhibition of proinflammatory cytokine production.
Xiao ZY, Zhou WX, Zhang YX, Cheng JP, He JF, Yang RF, Yun LH.
Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Haidian District, Beijing 100850, PR China.
Abstract
Roquinimex is an immunomodulator that can effectively inhibit the development of several autoimmune diseases in animal models, but the mechanism is still unknown. In this study, we investigated the effect of roquinimex on chronic graft-versus-host disease (GVHD) in mice, a well-established model for human systemic lupus erythematosus (SLE). Oral
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administration of roquinimex significantly suppressed the development of proteinuria and ameliorated nephritis symptoms in chronic GVHD mice. In addition, renal histopathology and immunohistochemistry studies revealed reduced glomerulonephritis and decreased IgG deposition in chronic GVHD mice treated with roquinimex. Chronic GVHD is characterized by a predominance of Th2 cytokines, and proinflammatory cytokines that also play an important role in the pathology of tissue damage. Therefore, we focused on the effect of roquinimex on cytokine production. Chronic GVHD mouse splenocytes exhibited severely reduced interferon (IFN)-gamma production in response to Concanavalin (Con A) stimulation and an overt Th2 skewness. Roquinimex treatment, however, induced IFN-gamma production and restored the Th1/Th2 cytokine balance, although only a minimal effect of roquinimex on interleukin (IL)-4 secretion was observed. The production of the proinflammatory cytokines TNF-alpha and IL-1 beta by peritoneal macrophages from lipopolysaccharide (LPS)-treated GVHD mice was significantly inhibited by roquinimex treatment. These data suggested that the beneficial effect of roquinimex on lupus might, at least in part, result from a restoration of Th1/Th2 cytokine balance and inhibition of inflammatory cytokine production.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Adjuvants, Immunologic/pharmacology Adjuvants, Immunologic/therapeutic use Animals Antibodies, Antinuclear/blood Blood Urea Nitrogen Cells, Cultured Cholesterol/blood Chronic Disease Creatinine/blood Cytokines/metabolism* Enzyme-Linked Immunosorbent Assay Female Graft vs Host Disease/etiology Graft vs Host Disease/immunology Graft vs Host Disease/prevention & control* Hydroxyquinolines/pharmacology Hydroxyquinolines/therapeutic use* Immunoglobulin G/blood
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Immunoglobulin G/immunology Inflammation Mediators/metabolism* Kidney/drug effects Kidney/metabolism Kidney/pathology Macrophages/cytology Macrophages/drug effects Macrophages/metabolism Male Mice Mice, Inbred DBA Proteinuria/prevention & control Spleen/drug effects Spleen/metabolism Spleen/pathology Th1 Cells/drug effects* Th1 Cells/immunology Th1 Cells/metabolism Th2 Cells/drug effects Th2 Cells/immunology Th2 Cells/metabolism Triglycerides/blood Substances Adjuvants, Immunologic Antibodies, Antinuclear Cytokines Hydroxyquinolines Immunoglobulin G Inflammation Mediators Triglycerides Cholesterol Creatinine roquinimex
Mol Med. 2007 Nov-Dec;13(11-12):592-604.
39.
Increased expression of CD14 in macrophages after inhibition of the cholesterol biosynthetic pathway by lovastatin.
Frey T, De Maio A.
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Department of Physiology, Johns Hopkins University, Baltimore, Maryland, USA.
Abstract
Sepsis, which is the product of a poorly controlled inflammatory response, is a major health problem. Adequate therapies for sepsis are unavailable, and patient care is mainly supportive. Statins, widely used for the treatment of hypercholesterolemia, have been found to be antiinflammatory, but the mechanisms responsible for this alteration in the inflammatory response are not well understood. We investigated the effect of statins on CD14 expression, the major binding site for bacterial lipopolysaccharide (LPS) on the macrophage surface. CD14 is found in both a membrane-bound form on the cell surface (mCD14) and in a soluble variant in circulation (sCD14). Treatment of RAW 264.7 macrophages with lovastatin resulted in elevated mCD14 levels and decreased sCD14 levels after LPS stimulation. The increase in mCD14 was dependent on depletion of geranylgeranyl pyrophosphate (GGPP) and subsequent inhibition of Rho GTPases, whereas the effect of lovastatin on sCD14 was independent of this pathway. The increase in mCD14 expression correlated with an enhanced response to LPS, at least at the level of tumor necrosis factor (TNF)-alpha secretion. These results suggest that statin treatment can modulate macrophage functon, which may have an impact on inflammation and the outcome from sepsis.

Publication Types Research Support, N.I.H., Extramural MeSH Terms Animals Anticholesteremic Agents/pharmacology* Antigens, CD14/metabolism* Blotting, Northern Cell Line Cholesterol/biosynthesis* Lipopolysaccharides/pharmacology Lovastatin/pharmacology* Macrophages, Peritoneal/drug effects Macrophages, Peritoneal/metabolism* Mice Mice, Inbred C57BL Microscopy, Confocal Substances
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Anticholesteremic Agents Antigens, CD14 Lipopolysaccharides Cholesterol Lovastatin Grant Support GM 050878/GM/NIGMS NIH HHS/United States GM 073825/GM/NIGMS NIH HHS/United States
J Atheroscler Thromb. 2007 Aug;14(4):192-201. Epub 2007 Aug 29.
40.
Endothelial lipase is increased by inflammation and promotes LDL uptake in macrophages.

Yasuda T, Hirata K, Ishida T, Kojima Y, Tanaka H, Okada T, Quertermous T, Yokoyama M.
Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Japan.
Abstract
AIM: Endothelial lipase (EL) is a member of the lipoprotein lipase family that regulates HDL metabolism. EL is known to act as a bridging molecule for monocytes or lipoproteins in vascular endothelial cells. We investigated the role and regulatory mechanisms of EL expression in macrophages. METHODS: Macrophages originating from wild-type (EL+/+) and EL-deficient (EL-/-) mice were stimulated with lipopolysaccharide (LPS). The expression of EL mRNA was evaluated by northern blotting. DiI-LDL was used to measure the uptake of native lowdensity lipoprotein (nLDL). RESULTS: LPS increased EL mRNA levels by increasing intracellular oxidative stress in the macrophages. LPS did not affect EL expression in macrophages derived from Tolllike receptor 4 (TLR4) gene mutant mice, C3H/HeJ. The uptake of nLDL after LPStreatment was significantly lower in macrophages from EL-/- mice than those from EL+/+ mice. Simvastatin suppressed the LPS-induced upregulation of EL expression and uptake of nLDL. CONCLUSIONS: EL expression is upregulated by LPS via TLR4 and promotes the uptake of nLDL by macrophages. Simvastatin inhibits the LPS-induced up-regulation and uptake in macrophages. Thus, our findings provide a novel role for EL in lipoprotein metabolism and would expand the range of anti-atherogenic effects of statins.
MeSH Terms, Substances
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MeSH Terms Animals Cholesterol, LDL/metabolism* Endothelium, Vascular/enzymology Endothelium, Vascular/immunology* Gene Expression Regulation, Enzymologic/drug effects Gene Expression Regulation, Enzymologic/immunology Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology Lipase/genetics Lipase/metabolism* Lipopolysaccharides/pharmacology Macrophages/drug effects Macrophages/immunology Macrophages/metabolism* Mice Mice, Inbred C3H Mice, Inbred C57BL Oxidative Stress/immunology Reactive Oxygen Species/metabolism Simvastatin/pharmacology Toll-Like Receptor 4/metabolism Vasculitis/immunology* Vasculitis/metabolism* Substances Cholesterol, LDL Hydroxymethylglutaryl-CoA Reductase Inhibitors Lipopolysaccharides Reactive Oxygen Species Tlr4 protein, mouse Toll-Like Receptor 4 Simvastatin Lipg protein, mouse Lipase
Circ Res. 2005 Oct 28;97(9):922-7. Epub 2005 Sep 22.
41.
Apolipoprotein E suppresses the type I inflammatory response in vivo.

Ali K, Middleton M, Pur E, Rader DJ.
Institute for Translational Medicine and Therapeutics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA.
14-10-2012
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Abstract
Apolipoprotein E (apoE) is synthesized in the liver and in macrophages, and it has antiatherogenic properties that are mediated, at least in part, through the regulation of plasma cholesterol homeostasis. Previous data suggest that apoE also has antiinflammatory properties that may contribute to protection against atherosclerosis independent of its role in lipid metabolism. In this study, apoE knockout and C57BL/6 mice were stimulated with low-dose lipopolysaccharide (LPS) and other Toll-like receptor (TLR) agonists. We show that apoE modulates the systemic type I inflammatory response in vivo. The proinflammatory cytokines tumor necrosis factor alpha, interleukin (IL)-6, IL-12, and interferon-gamma were upregulated to a significantly greater extent in apoE-deficient mice than in wild-type mice at both the mRNA and protein levels following administration of LPS. In contrast, hypercholesterolemic low-density lipoprotein receptor/apobec-1 double knockout mice had a similar cytokine response as wild-type mice, eliminating hypercholesterolemia as a cause for the exaggerated cytokine response. Importantly, reconstitution of apoE expression in the liver of apoE-deficient mice normalized the LPSinduced plasma protein levels of IL-12p40. Furthermore, there was selective upregulation of plasma IL-12 in apoE knockout mice by a TLR3 agonist, poly I:C, but not by other TLR agonists, CpG oligonucleotide or Toxoplasma gondii antigen. This implies that apoE selectively regulates TLR4- and TLR3-mediated signaling of IL-12 production. These results indicate that apoE modulates the T helper-1-type immune response in vivo by modulating IL-12 production.

Publication Types Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S. MeSH Terms Animals Apolipoproteins E/physiology* Female Inflammation/prevention & control* Interleukin-12/biosynthesis* Interleukin-12/blood Interleukin-12/genetics Interleukin-6/blood Interleukin-6/genetics Lipopolysaccharides/pharmacology Mice
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Mice, Inbred C57BL Poly I-C/pharmacology RNA, Messenger/analysis Signal Transduction Th1 Cells/immunology* Toll-Like Receptor 3/physiology Tumor Necrosis Factor-alpha/analysis Tumor Necrosis Factor-alpha/genetics Substances Apolipoproteins E Interleukin-6 Lipopolysaccharides RNA, Messenger Toll-Like Receptor 3 Tumor Necrosis Factor-alpha Interleukin-12 Poly I-C Grant Support HL07433-26/HL/NHLBI NIH HHS/United States HL22633-27/HL/NHLBI NIH HHS/United States HL59407/HL/NHLBI NIH HHS/United States HL62250-06/HL/NHLBI NIH HHS/United States HL70128/HL/NHLBI NIH HHS/United States
J Steroid Biochem Mol Biol. 2005 Dec;97(4):376-83. Epub 2005 Sep 16.
42.
Suppression of inducible nitric oxide synthase and cyclooxygenase-2 gene expression by 22(R)hydroxycholesterol requires de novo protein synthesis in activated macrophages.
Yasuda T, Kanno M, Kawamoto M, Yuge O, Ninomiya Y.
Department of Anesthesiology and Critical Care, Hiroshima University, 1-2-3, kasumi, Hiroshima 734-8551, Japan.
Abstract
Liver X receptors (LXRs) play an important role in lipid metabolism. Recently, a role for these proteins was identified in suppressing the inflammatory response. However, it is not known whether the natural ligands of LXRs, e.g. 22(R)-hydroxycholesterol (22R-HC), can suppress the inflammatory response after the onset of inflammation. We demonstrate here that treatment of Lipopolysaccharide (LPS)-activated RAW264.7 macrophages with
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22R-HC markedly suppressed nitric oxide (NO) production and inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expression. Additionally, 22R-HC did not affect the DNA binding activity of NF-kappaB, AP-1 and C/EBP(s), important transcriptional factors for iNOS and COX-2 genes expression. Furthermore iNOS and COX-2 mRNA suppression by 22R-HC was diminished by cellular treatment with cycloheximide. These results suggest that 22R-HC suppresses the expression of iNOS and COX-2 genes through de novo protein synthesis of an unidentified protein in LPSactivated macrophages.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals CCAAT-Enhancer-Binding Proteins/metabolism Cell Line Cells, Cultured Cyclooxygenase 2/metabolism* Cyclooxygenase Inhibitors/pharmacology* DNA/chemistry DNA-Binding Proteins/metabolism Gene Expression Regulation, Enzymologic* Glucocorticoids/metabolism Hydroxycholesterols/pharmacology* Inflammation Ligands Lipopolysaccharides/chemistry Lipopolysaccharides/metabolism Macrophage Activation Macrophages/metabolism* Mice Models, Statistical NF-kappa B/metabolism Nitric Oxide/metabolism Nitric Oxide Synthase Type II/antagonists & inhibitors* Nitrites/metabolism Orphan Nuclear Receptors Protein Binding
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Proteins/metabolism* RNA/chemistry RNA/metabolism RNA, Messenger/metabolism Receptors, Cytoplasmic and Nuclear/metabolism Time Factors Transcription Factor AP-1/metabolism Transcription, Genetic Substances CCAAT-Enhancer-Binding Proteins Cyclooxygenase Inhibitors DNA-Binding Proteins Glucocorticoids Hydroxycholesterols Ligands Lipopolysaccharides NF-kappa B Nitrites Orphan Nuclear Receptors Proteins RNA, Messenger Receptors, Cytoplasmic and Nuclear Transcription Factor AP-1 liver X receptor Nitric Oxide 22-hydroxycholesterol RNA DNA Nitric Oxide Synthase Type II Cyclooxygenase 2
Crit Care Med. 2005 Aug;33(8):1688-93.
43.
Low serum level of high-density lipoprotein cholesterol is a poor prognostic factor for severe sepsis.
Chien JY, Jerng JS, Yu CJ, Yang PC.
Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch , Douliu, Taiwan.
Erratum in
Crit Care Med. 2005 Nov;33(11):2727.
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Abstract
OBJECTIVE: To assess the initial serum levels of lipids and lipoproteins and their correlations with the clinical outcome for patients with severe sepsis. The ability of highdensity lipoprotein (HDL) to attenuate lipopolysaccharide (LPS)-induced cytokine production was also examined in vitro. DESIGN: Prospective, observational cohort study. SETTING: Medical intensive care unit (ICU) of a tertiary-level university hospital. PATIENTS: Sixty-three consecutive patients with severe sepsis. INTERVENTIONS: Blood samples were drawn within the first day of severe sepsis and the subsequent 14 days. Clinical outcome, including length of ICU stay, infection subsequent to hospital stay, and death, were monitored prospectively. MEASUREMENTS AND RESULTS: Compared with the survivors, patients who died within 30 days had significantly lower levels of HDL cholesterol and apolipoprotein A-I during the first 4 days of severe sepsis. On day 1, HDL cholesterol levels correlated inversely with interleukin-6 (r = -0.72; p < .01) and tumor necrosis factor (TNF)-alpha (r = 0.70; p < .01) concentrations. Not only the overall and sepsis-attributable 30-day mortality rates but also the risk of prolonged ICU stay (>7 days) and the hospital-acquired infection rate were increased among patients with day 1 levels of HDL cholesterol of <20 mg/dL and apolipoprotein A-I of <100 mg/dL. Multivariate analysis identified an HDL cholesterol level of <20 mg/dL on day 1 (odds ratio, 12.92; 95% confidence interval, 2.73-61.29) and Acute Physiology and Chronic Health Evaluation II score (odds ratio, 1.15; 95% confidence interval, 1.04-1.26) as independent predictors of the overall 30-day mortality rate. In human macrophages, LPS-induced TNF-alpha release was attenuated by incremental doses of HDL cholesterol added simultaneously (p < .01). However, HDL failed to suppress LPS-induced TNF-alpha production when administered after macrophages were exposed to LPS. CONCLUSIONS: A low HDL cholesterol level on day 1 of severe sepsis is significantly associated with an increase in mortality and adverse clinical outcomes. In cultured macrophages, HDL can attenuate LPS-induced TNF-alpha production only if added concomitantly with, but not after, LPS exposure.
Comment in
Lipoproteins are protective beyond high-density lipoprotein cholesterol and heart disease. [Crit Care Med. 2005]

Publication Types In Vitro Research Support, Non-U.S. Gov't
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MeSH Terms Adolescent Adult Aged Aged, 80 and over Apolipoprotein A-I/blood Biological Markers Cholesterol, HDL/blood* Cholesterol, HDL/immunology Cytokines/blood Female Humans Lipopolysaccharides Male Middle Aged Multivariate Analysis Prognosis Prospective Studies Regression Analysis Sepsis/diagnosis* Sepsis/immunology Sepsis/mortality Taiwan/epidemiology Substances Apolipoprotein A-I Biological Markers Cholesterol, HDL Cytokines Lipopolysaccharides
Indian J Exp Biol. 2005 Jun;43(6):509-16.
44.
Extract of gum resins of Boswellia serrata L. inhibits lipopolysaccharide induced nitric oxide production in rat macrophages along with hypolipidemic property.
Pandey RS, Singh BK, Tripathi YB.
Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India.
Abstract
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Boswellia serrata, Linn F (Burseraceae) is commonly used in Indian system of medicine (Ayurvedic) as an anti-inflammatory, analgesic, anti-arthritic and anti-proliferative agent. This study was planned to investigate the water-soluble fraction of the oleoresin gum of Boswellia serrata (BS extract) on lipopolysaccharide (LPS) induced nitric oxide (NO) production by macrophages under in vivo and in vitro conditions. In the previous condition, rats were fed on atherogenic diet (2.5% cholesterol, 1% cholic acid, 15.7 % saturated fat) along with the BS extract for 90 days. Blood was collected for lipid profile and toxicological safety parameters. Peritoneal macrophages were isolated and cultured to see the LPS induced NO production. Under in vivo experiment, BS extract significantly reduced serum total cholesterol (38-48 %), increased serum high-density lipoproteincholesterol (HDL-cholesterol, 22-30%). Under in vitro experiments with thioglycolate activated macrophages, it inhibited LPS induced (NO) production with IC 50 value at 662 ng /ml. Further, this fraction, in the dose of 15 mg/100 g body wt for 90 days, did not show any increase in serum glutamate-pyruvate transaminase (SGPT) and blood urea, in normal control animals. However, it significantly reversed the raised SGPT and blood urea in the atherogenic diet-fed animals. Transverse section of liver and kidney also supported its protective effect. Thus it may be concluded that water extract of Boswellia serrata possesses strong hypocholesterolemic property along with increase in serum HDL. It inhibits the LPS induced NO production by the activated rat peritoneal macrophages and show hepato-protective and reno-protective property.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals Anti-Inflammatory Agents/pharmacology Anticholesteremic Agents/pharmacology Boswellia/metabolism* Cell Proliferation Cell Survival Cells, Cultured Cholesterol/metabolism Diet, Atherogenic Inflammation Inhibitory Concentration 50 Kidney/metabolism Kidney/pathology Lipid Metabolism Lipids/chemistry Lipopolysaccharides/chemistry*
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Liver/metabolism Liver/pathology Macrophages/cytology Macrophages/metabolism* Macrophages, Peritoneal/metabolism Nitric Oxide/chemistry Nitric Oxide/metabolism* Plant Structures/chemistry Rats Resins, Plant/metabolism Time Factors Transaminases/blood Urea/blood Water/chemistry Water/metabolism Substances Anti-Inflammatory Agents Anticholesteremic Agents Lipids Lipopolysaccharides Resins, Plant Nitric Oxide Urea Cholesterol Water Transaminases phosphoserine aminotransferase
Immunol Res. 2005;31(3):243-60.
45.
The proteasome: a central regulator of inflammation and macrophage function.

Qureshi N, Vogel SN, Van Way C 3rd, Papasian CJ, Qureshi AA, Morrison DC.
Department of Basic Medical Science, School of Medicine, Shock/Trauma Research Center, University of Maryland-Baltimore, Baltimore, MD, USA. qureshin@umkc.edu
Abstract
Proteasomes, multisubunit complexes that consist of a 20S proteasome and a 19S regulatory complex, are essential for several cellular processes. Our interest in the proteasome complex stems from our observations that a novel photoactivable lipopolysaccharide (LPS) probe binds to specific proteasome subunits, and that LPS
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enhances the chymotrypsin-like activity of the proteasome to degrade synthetic peptides in vitro. Experiments with proteasome inhibitors have shown that expression of many LPS -inducible genes, including TLR2, is inhibited in macrophages. More important, proteasome inhibitors such as lactacystin can prevent LPS-induced shock in mice. This article focuses on the role of the proteasome in the development of inflammatory processes, which may result in septic shock, hemorrhagic shock, atherosclerosis, and neurodegenerative disorders. Taken collectively, the results suggest a potentially important role of the proteasome in inflammation and other macrophage functions.

Publication Types Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S. Review MeSH Terms Acetylcysteine/analogs & derivatives Acetylcysteine/pharmacology Aging/immunology Animals Atherosclerosis/immunology Cholesterol/biosynthesis Humans Inflammation/immunology Inflammation/metabolism Lipopolysaccharides/immunology Macrophages/immunology Macrophages/physiology* Mice Neurodegenerative Diseases/immunology Proteasome Endopeptidase Complex/antagonists & inhibitors Proteasome Endopeptidase Complex/physiology* Shock, Hemorrhagic/immunology Signal Transduction Toll-Like Receptor 2/biosynthesis Substances Lipopolysaccharides Toll-Like Receptor 2
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lactacystin Cholesterol Acetylcysteine Proteasome Endopeptidase Complex Grant Support AI 18797/AI/NIAID NIH HHS/United States AI 23447/AI/NIAID NIH HHS/United States GM 50870/GM/NIGMS NIH HHS/United States
Psychoneuroendocrinology. 2004 Oct;29(9):1119-28.
46.
Enhanced expression of cytokines and chemokines by blood monocytes to in vitro lipopolysaccharide stimulation are associated with hostility and severity of depressive symptoms in healthy women.
Suarez EC, Lewis JG, Krishnan RR, Young KH.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, P.O. Box 3328, Durham, NC 27710, USA. ecs.jr@duke.edu
Abstract
The current study investigated the relation of hostility and severity of depressive symptoms, separately and jointly, to the capacity of blood monocytes to secrete an array of cytokines when stimulated by bacterial lipopolysaccharide (LPS). Subjects were 44 healthy, non-smoking, premenopausal women (aged 23-49 years) not currently taking oral contraceptives. Data were collected during the follicular phase of the menstrual cycle. The Cook-Medley Hostility (Ho) scale and the Beck Depression Inventory (BDI) were used to assess hostility and severity of depressive symptoms, respectively. Dual-color flow cytometry was used to measure the total expression of interleukin (IL)-1alpha, IL-1beta, IL -8, tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP)-1 and monocyte inflammatory protein (MIP)-1alpha in blood monocytes following 4 h in vitro LPS stimulation of whole blood. In analyses adjusting for age, body mass index (BMI), fasting cholesterol, alcohol use, race and 17beta-estradiol (E(2)), higher Ho scores were associated with greater LPS-stimulated expression of IL-1alpha (beta = 0.033, p = 0.02), IL-8 (beta = 0.046, p = 0.01) and IL-1beta (beta = 0.024, p = 0.06). Higher BDI scores were associated with greater expression of TNF-alpha (beta = 0.042, p = 0.02) and IL-8 (beta = 0.045, p = 0.04). The linear combination of Ho and BDI scores was significantly associated with IL-1beta (beta = 0.18, p = 0.057), IL-8 (beta = 0.36, p = 0.01), TNF-alpha (beta = 0.25, p = 0.03), and IL-1alpha (beta = 0.18, p < 0.07). Thus, in healthy women, these psychological risk factors, alone and in combination, induce a proinflammatory phenotype in circulating monocytes characterized by the up-regulation of proinflammatory cytokines, supporting the hypothesis that inflammation may be a key pathway whereby
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hostility and depressive symptoms contribute to atherosclerosis and subsequent coronary heart disease (CHD).

Publication Types Clinical Trial Comparative Study Research Support, U.S. Gov't, P.H.S. MeSH Terms Cells, Cultured/drug effects Chemokine CCL2/metabolism Chemokine CCL3 Chemokine CCL4 Chemokines/metabolism Cytokines/metabolism* Depression/blood Depression/immunology Depression/metabolism* Emotions/physiology Estradiol/blood Female Hostility* Humans Interleukin-1/metabolism Interleukin-8/metabolism Lipopolysaccharides/pharmacology* Macrophage Inflammatory Proteins/metabolism Monensin/pharmacology Monocytes/immunology Monocytes/metabolism* Neuropsychological Tests Reference Values Regression Analysis Risk Factors Severity of Illness Index Tumor Necrosis Factor-alpha/metabolism Up-Regulation
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Substances Chemokine CCL2 Chemokine CCL3 Chemokine CCL4 Chemokines Cytokines Interleukin-1 Interleukin-8 Lipopolysaccharides Macrophage Inflammatory Proteins Tumor Necrosis Factor-alpha Monensin Estradiol Grant Support HL-56105/HL/NHLBI NIH HHS/United States HL-67459/HL/NHLBI NIH HHS/United States
J Immunol. 2004 Jun 15;172(12):7377-84.
47.
Simvastatin augments lipopolysaccharide-induced proinflammatory responses in macrophages by differential regulation of the c-Fos and c-Jun transcription factors.
Matsumoto M, Einhaus D, Gold ES, Aderem A.
Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103-8904, USA.
Abstract
The 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are a widely used class of drugs for cholesterol reduction. The reduction in mortality and morbidity in statin-treated patients is incompletely explained by their effects on cholesterol, and an anti-inflammatory role for the drug has been proposed. We report in this work that, unexpectedly, simvastatin enhances LPS-induced IL-12p40 production by murine macrophages, and that it does so by activating the IL-12p40 promoter. Mutational analysis and dominant-negative expression studies indicate that both C/EBP and AP-1 transcription factors have a crucial role in promoter activation. This occurs via a c-Fosand c-Jun-based mechanism; we demonstrate that ectopic expression of c-Jun activates the IL-12p40 promoter, whereas expression of c-Fos inhibits IL-12p40 promoter activity. Simvastatin prevents LPS-induced c-Fos expression, thereby relieving the inhibitory effect of c-Fos on the IL-12p40 promoter. Concomitantly, simvastatin induces the phosphorylation of c-Jun by the c-Jun N-terminal kinase, resulting in c-Jun-dependent activation of the IL-12p40 promoter. This appears to be a general mechanism because simvastatin also augments LPS-dependent activation of the TNF-alpha promoter, perhaps because the TNF-alpha promoter has C/EBP and AP-1 binding sites in a similar
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configuration to the IL-12p40 promoter. The fact that simvastatin potently augments LPSinduced IL-12p40 and TNF-alpha production has implications for the treatment of bacterial infections in statin-treated patients.

Publication Types Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. MeSH Terms Adjuvants, Immunologic/pharmacology Animals CCAAT-Enhancer-Binding Proteins/physiology Drug Synergism Female Gene Expression Regulation/drug effects Gene Expression Regulation/immunology* Inflammation/chemically induced* Interleukin-12/biosynthesis Interleukin-12 Subunit p40 Lipopolysaccharides/pharmacology* Macrophages/drug effects Macrophages/immunology* Mice Mice, Inbred C57BL Promoter Regions, Genetic/drug effects Protein Subunits/biosynthesis Proto-Oncogene Proteins c-fos/genetics Proto-Oncogene Proteins c-fos/physiology Proto-Oncogene Proteins c-jun/genetics Proto-Oncogene Proteins c-jun/physiology Simvastatin/pharmacology* Transcription Factor AP-1/physiology Transcription Factors/genetics* Transcription Factors/physiology Substances Adjuvants, Immunologic CCAAT-Enhancer-Binding Proteins
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Interleukin-12 Subunit p40 Lipopolysaccharides Protein Subunits Proto-Oncogene Proteins c-fos Proto-Oncogene Proteins c-jun Transcription Factor AP-1 Transcription Factors Interleukin-12 Simvastatin Grant Support 1K08 HL 71582/HL/NHLBI NIH HHS/United States AO 25032/AO/NIAID NIH HHS/United States
Nat Med. 2004 Apr;10(4):416-21. Epub 2004 Mar 14.
48.
Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways.
Bjrkbacka H, Kunjathoor VV, Moore KJ, Koehn S, Ordija CM, Lee MA, Means T, Halmen K, Luster AD, Golenbock DT, Freeman MW.
Lipid Metabo lism Unit, Massachusetts General Ho spital, Harvard Medical Schoo l, Boston, Massachusetts 02114, USA.
Abstract
Athero sclerosis, the leading cause of death in developed countries, has been linked to hypercholesterolemia for decades. More recently, atherosclerotic lesion progression has been shown to depend on persistent, chro nic inflammation in the artery wall. Although several studies have implicated infectious agents in this process, the role o f infection in atherosclerosis remains controversial. Because the involvement of mo nocytes and macrophages in the pathogenesis of atherosclerosis is well established, we investigated the possibility that macrophage innate immunity signaling pathways normally activated by pathogens might also be activated in response to hyperlipidemia. We examined atherosclerotic lesion develo pment in uninfected, hyperlipidemic mice lacking expression of either lipopolysaccharide (LPS) receptor CD14 or myeloid differentiation protein-88 (MyD88), which transduces cell signaling events do wnstream of the Toll-like receptors (TLRs), as well as receptors for interleukin-1 (IL-1) and IL-18. Whereas the MyD88deficient mice evinced a marked reduction in early atherosclerosis, mice deficient in CD14 had no decrease in early lesion development. Inactivation of the MyD88 pathway led to a reduction in atherosclerosis through a decrease in macrophage recruitment to the artery wall that was associated with reduced chemokine levels. These findings link elevated serum lipid levels to a proinflammatory signaling cascade that is also engaged by microbial pathogens.
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Publication Types Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. MeSH Terms Animals Arteriosclerosis/blood Arteriosclerosis/genetics* Cholesterol/blood* Immunity, Innate* Mice Mice, Inbred C57BL Mice, Knockout Signal Transduction* Substances Cholesterol Grant Support DK50305/DK/NIDDK NIH HHS/United States HL45098/HL/NHLBI NIH HHS/United States HL66678/HL/NHLBI NIH HHS/United States RR14466/RR/NCRR NIH HHS/United States
Lab Invest. 2004 Apr;84(4):425-32.
49.
Recurrent perivascular inflammation induced by lipopolysaccharide (endotoxin) results in the formation of atheromatous lesions in vivo.
Engelmann MG, Redl CV, Nikol S.
Medical Department I, Klinikum Grosshadern, Ludwig Maximilian University, Marchioninistrasse 15, Munich 81377, Germany. markus.engelmann@med.uni-muenchen.de
Abstract
Bacteria and viruses are suspected to induce arteriosclerosis; however, most investigators have focused on coincidences rather than causal relationships. The aim of this work was to establish a rabbit model in which the vessel reaction to local perivascular injection of
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defined bacterial products can be analyzed. A total of 23 rabbits were randomized to four groups. Groups A and B were fed a normal diet, groups C and D were fed a cholesterolenriched diet. Groups A and C were treated with a single perivascular injection of bacterial lipopolysaccharide (LPS, endotoxin) placed next to auricular, carotid and femoral arteries, and sodium chloride placed next to the contralateral arteries (control). Group B and D animals were treated with repeated perivascular injections over 90 days. Vascular tissues (n=116 treated segments of 23 rabbits) were analyzed using morphometry at histology, and using immunohistochemistry to detect macrophages, lymphocytes and vascular smooth muscle cells. LPS treatment resulted in transient focal intima thickening. After single LPS application, no increase in atheromatous lesion formation was observed in comparison with controls (group C, lesion area index 0.031+/-0.012 vs 0.015+/-0.006, P=1.0). Repeated LPS application resulted in significant atheromatous lesion formation compared with saline control (group D, lesion area index 0.148+/-0.049 vs 0.008+/-0.006, P=0.003) in hypercholesterolemic rabbits. Repeated LPS inflammation in normocholesterolemic did not lead to atheromatous lesion formation (intima media ratio 0.04+/-0.01 vs 0.04+/-0.007, P=1.0). Single perivascular administration of low-dose bacterial LPS resulted in transient focal intimal thickening, while significant increase in lesion formation occurred after repeated LPS application in cholesterol-fed animals. In conclusion, this animal model will allow the assessment of the impact of defined dosages of different bacterial pathogens onto the vascular wall in the context of atherogenesis. The atheromatous lesion-promoting effect of repeated perivascular administration of LPS supports the hypothesis that bacterial pathogens may be involved in atherogenesis.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals Arteriosclerosis/etiology* Female Inflammation/complications* Lipopolysaccharides/toxicity* Rabbits Recurrence Tunica Intima/drug effects Tunica Intima/pathology Substances Lipopolysaccharides
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J Cardiovasc Pharmacol. 2003 Aug;42(2):287-95.
50.
Hematein inhibits atherosclerosis by inhibition of reactive oxygen generation and NF-kappaB-dependent inflammatory mediators in hyperlipidemic mice.
Choi JH, Jeong TS, Kim DY, Kim YM, Na HJ, Nam KH, Lee SB, Kim HC, Oh SR, Choi YK, Bok SH, Oh GT.
Department of Veterinary Pathology, College of Veterinary Medicine and Agricultural Biotechnology, Seoul National University, Suwon, Korea.
Abstract
Hematein, a natural compound, is a known anti-inflammatory and antiatherogenic agent in the rabbit model. The authors investigated the effects of this compound on atherogenesis and possible mechanisms of the actions in the hyperlipidemic mice. Low-density lipoprotein receptor-deficient (Ldlr-/-) mice fed a high-cholesterol diet alone for 8 weeks developed the fatty streak lesion in the aortic sinus, whereas this lesion was significantly reduced by hematein treatment without a change in plasma lipid levels compared with control mice. Hematein treatment reduced plasma levels of lipid peroxide and superoxide generation in LPS-stimulated peritoneal macrophage. Hematein treatment inhibited NFkappaB-DNA binding activity in peritoneal macrophages from Ldlr-/- mice and the activation of NF-kappaB in RAW264.7 macrophages. This compound suppressed plasma nitrite/nitrate levels in Ldlr-/- mice and NO production and iNOS expression in LPS+IFNgamma-stimulated peritoneal macrophages. Hematein treatment also suppressed the activity of iNOS promoters in RAW264.7 macrophages, and reduced the plasma levels of TNF-alpha and IL-1beta and the production of these cytokines in LPS+IFNgamma-stimulated peritoneal macrophages. These results suggest that hematein inhibits atherosclerotic lesion formation, possibly by reducing proinflammatory mediators through a decrease in reactive oxygen species generation and NF-kappaB activation.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Animals Arteriosclerosis/prevention & control* Cholesterol, Dietary/blood* Female Hematoxylin/analogs & derivatives*
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Hematoxylin/therapeutic use* Inflammation Mediators/therapeutic use* Macrophages, Peritoneal/drug effects Macrophages, Peritoneal/metabolism Mice NF-kappa B/antagonists & inhibitors* Reactive Oxygen Species/antagonists & inhibitors* Substances Cholesterol, Dietary Inflammation Mediators NF-kappa B Reactive Oxygen Species hematein Hematoxylin
Eur J Clin Invest. 2002 Jan;32(1):35-42.
51.
Oxysterols induce interleukin-1beta production in human macrophages.

Rosklint T, Ohlsson BG, Wiklund O, Norn K, Hultn LM.
Sahlgrenska University Hospital, Gteborg University, Gteborg, Sweden.
Abstract
BACKGROUND: Oxysterols are biologically active molecules generated during the oxidation of low-density lipoprotein or formed enzymatically in vivo. In the atherosclerotic plaque newly recruited macrophages may be exposed to oxysterols present in the plaque. How these oxysterols affect the expression and secretion of inflammatory cytokines such as interleukin-1beta (IL-1beta) in macrophages is not known. Therefore the aim of the present study was to investigate how oxysterols regulate the expression and secretion of IL-1beta in human monocyte-derived macrophages. METHODS: The IL-1beta messenger RNA (mRNA) expression was analysed by reverse transcription-polymerase chain reaction, and the IL-1beta protein secretion was measured by enzyme-linked immunosorbent assay. RESULTS: A significant, dose-dependent increase in the secretion of IL-1beta was given by 25-hydroxycholesterol without the addition of lipopolysaccharide (LPS). At a concentration of 2.5 microg mL(-1) this increase was similar to that obtained by endotoxin (LPS, 1 microg mL(-1)). A transient increase in IL-1beta mRNA expression was found in macrophages incubated with 25-hydroxycholesterol compared with untreated controls. In addition, 25-hydroxycholesterol dramatically increased the IL-1beta secretion induced by LPS. At a concentration of 5 microg mL(-1) of 25-hydroxycholesterol the LPS-induced IL-
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1beta secretion was increased by about 25-fold. A similar tendency, but not so consistent, was found for 27-hydroxycholesterol. CONCLUSIONS: Our results show that oxysterols, and 25-hydroxycholesterol in particular, may modulate the inflammatory response in human macrophages. Consequently the presence of oxysterols in atherosclerotic tissue may dramatically influence the effect of inflammation.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Arteriosclerosis/physiopathology Caspase 1/metabolism Cells, Cultured Gene Expression/physiology Humans Hydroxycholesterols/pharmacology* Interleukin-1/genetics* Interleukin-1/secretion Interleukin-6/metabolism Lipopolysaccharides/pharmacology Macrophages/cytology Macrophages/drug effects Macrophages/physiology* RNA, Messenger/analysis Substances Hydroxycholesterols Interleukin-1 Interleukin-6 Lipopolysaccharides RNA, Messenger 27-hydroxycholesterol 25-hydroxycholesterol Caspase 1
J Lipid Res. 2001 Oct;42(10):1636-44.
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52.
Regulation of scavenger receptor class B type I in hamster liver and Hep3B cells by endotoxin and cytokines.
Khovidhunkit W, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR.
Metabolism Section, Department of Veterans Affairs Medical Center, 4150 Clement Street, Box 111 F, San Francisco, CA 94121, USA. wkhovid@itsa.ucsf.edu
Abstract
Multiple changes in HDL metabolism occur during infection and inflammation that could potentially impair the antiatherogenic functions of HDL. Scavenger receptor class B type I (SR-BI) promotes cholesterol efflux from peripheral cells and mediates selective uptake of cholesteryl ester into hepatocytes, thereby playing a pivotal role in reverse cholesterol transport. We studied the effect of endotoxin (lipopolysaccharide, LPS) and cytokines [tumor necrosis factor (TNF) and interleukin 1 (IL-1)] on hepatic SR-BI mRNA and protein levels in Syrian hamsters. LPS significantly decreased SR-BI mRNA levels in hamster liver. This effect was rapid and sustained, and was associated with a decrease in hepatic SR-BI protein levels. High cholesterol diet did not change hepatic SR-BI mRNA levels, and LPS was able to decrease SR-BI mRNA levels during high cholesterol feeding. TNF and IL-1 decreased SR-BI mRNA levels in the liver, and the effects of TNF and IL-1 were additive. TNF and IL-1 also decreased SR-BI levels in Hep3B hepatoma cells. More importantly, TNF and IL-1 decreased the uptake of HDL cholesteryl ester into Hep3B cells. In addition, we studied the effect of LPS on SR-BI mRNA in RAW 264.7 cells, a macrophage cell line. LPS rapidly decreased SR-BI mRNA levels in RAW 264.7 cells, but the effect was not sustained and did not lead to a reduction in SR-BI protein levels. Our results suggest that the decrease in hepatic SR-BI levels due to LPS and cytokines during infection and inflammation may decrease selective uptake of cholesteryl ester into the liver and result in impaired reverse cholesterol transport.

Publication Types Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. MeSH Terms Animals Antigens, CD36/genetics Antigens, CD36/metabolism* Cholesterol Esters/metabolism Cricetinae Diet Hepatocytes/drug effects*
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Hepatocytes/metabolism Humans Inflammation/metabolism Interleukin-1/pharmacology* Lipid Metabolism Lipopolysaccharides/pharmacology* Lipoproteins/metabolism Liver/drug effects* Liver/metabolism* Macrophages/drug effects Macrophages/metabolism Membrane Proteins* Mice RNA, Messenger/genetics RNA, Messenger/metabolism Receptors, Immunologic* Receptors, Lipoprotein* Receptors, Scavenger Scavenger Receptors, Class B Time Factors Tumor Cells, Cultured Tumor Necrosis Factor-alpha/pharmacology* Substances Antigens, CD36 Cholesterol Esters Interleukin-1 Lipopolysaccharides Lipoproteins Membrane Proteins RNA, Messenger Receptors, Immunologic Receptors, Lipoprotein Receptors, Scavenger SCARB1 protein, human Scarb1 protein, mouse Scavenger Receptors, Class B Tumor Necrosis Factor-alpha
Biochem Biophys Res Commun. 1999 Aug 19;262(1):251-4.
53.
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Lipopolysaccharide inhibits the expression of the scavenger receptor Cla-1 in human monocytes and macrophages.
Buechler C, Ritter M, Quoc CD, Agildere A, Schmitz G.
Klinikum der Universitt Regensburg, Regensburg, D-93042, Germany.
Abstract
Human Cla-1 is the likely homologue of the murine scavenger receptor class B type I (SRBI). SR-BI mediates selective transfer of cholesterol to high-density lipoprotein (HDL) and the efflux of endogenously synthesized and plasma membrane sterols to HDL. HDL protects against atherosclerosis but also reduces endotoxic activity by complexa tion and neutralization of LPS. We found that Cla-1 is upregulated during phagocytic as well a s dendritic differentiation of monocytes, indicating a function of this receptor for cholesterol homeostasis in phagocytes and antigen-presenting cells. Cla-1 expression is suppressed by the proinflammatory stimuli lipopolysaccharide, interferon-gamma, and tumor necrosis factor alpha in monocytes and macrophages. Downregulation of Cla-1 mRNA by LPS is likely due to a modification and subsequent desta bilization of the mRNA. We propose that suppression of Cla-1 expression may help to stabilize the lipoprotein status in the blood compartment important for host defense. Copyright 1999 Academic Press.

Publication Types Research Support, Non-U.S. Gov't MeSH Terms Antigens, CD36/genetics* Cell Differentiation Cholesterol/metabolism Cycloheximide/pharmacology Cytokines/pharmacology Dactinomycin/pharmacology Dendritic Cells/cytology Dendritic Cells/drug effects Dendritic Cells/metabolism Gene Expression Regulation/drug effects* Half-Life Humans Inflammation Lipopolysaccharides/pharmacology* Lipoproteins/metabolism
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Macrophages/cytology Macrophages/drug effects Macrophages/metabolism* Monocytes/cytology Monocytes/drug effects Monocytes/metabolism* RNA, Messenger/genetics RNA, Messenger/metabolism Receptors, Immunologic/genetics* Receptors, Lipoprotein/genetics* Receptors, Scavenger Scavenger Receptors, Class B Substances Antigens, CD36 Cytokines Lipopolysaccharides Lipoproteins RNA, Messenger Receptors, Immunologic Receptors, Lipoprotein Receptors, Scavenger SCARB1 protein, human Scavenger Receptors, Class B Dactinomycin Cholesterol Cycloheximide
Herz. 1998 May;23(3):168-77.
54.
T-lymphocytes and monocytes in atherogenesis.

Schmitz G, Herr AS, Rothe G.
Institute for Clinical Chemistry and Laborary Medicine, University of Regensburg. gerd.schmitz@klink.uniregensburg.de
Abstract
Atherosclerosis is characterized as a chronic inflammatory-fibroproliferative disease of the vessel wall. The attachment of monocytes and T-lymphocytes to the injured endothelium followed by their migration into the intima is one of the first and most crucial steps in lesion development. The co-localization of CD4+ T-cells and macrophages in the lesion, the abundant expression of HLA Class II molecules and the co-stimulatory molecule CD40 and its ligand (CD40L) indicate a contribution of cell-mediated immunity to atherogenesis.
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Transgenic mouse models revealed that dependent on the model T- and B-cells may promote lesion progression, monocytes and macrophages are in contrast essential for the development of atherosclerotic lesions. Apart from the local process in the vessel wall, systemic signs of an inflammatory reaction are also associated with lesion development. Thus plasma levels of C-reactive protein and fibrinogen and the white blood cell count are positively correlated to the risk of cardiovascular disease. Recently, an inflammatory phenotype of circulating peripheral blood monocytes could be demonstrated as a specific cellular correlate to lipid and lipoprotein risk factors. Thus the pool size of LPS receptor (CD14)dim and Fc gamma IIIa receptor (CD16a)+ monocytes positively correlates to plasma cholesterol levels, to triglycerides levels and to the apolipoprotein E4 (apo E4) phenotype in contrast to a negative correlation to the high density lipoprotein (HDL) cholesterol concentration. This CD14dim CD16a+ monocytes are further characterized by a high expression of beta 1- and beta 2-integrins, suggesting a higher capacity for attachment at sites of inflammation. A proinflammatory cytokine pattern and an expansion of these cells in other inflammatory diseases are indicating that these cells promote the inflammatory process during atherogenesis. Surface expression of the activation antigen CD45RA on monocytes in correlation to plasma LDL cholesterol and Lp(a) levels further indicates an inflammatory reaction. Regarding the potential mechanisms of the phenotypic changes of peripheral blood monocytes, in a serum free in vitro differentiation model supplemented with M-CSF monocytes from probands which are homozygous for apo E4 showed a significantly higher increase of CD16a expression compared to apo E3/E3 cells indicating that a genetic polymorphism of a single apolipoprotein gene locus may affect monocyte differentiation. The further characterization of the cellular immunology of monocytes and T-lymphocytes in lesion development will provide new specific diagnostic and therapeutic targets in atherogenesis.
Publication Types, MeSH Terms

Publication Types Review MeSH Terms Animals Arteriosclerosis/immunology* Coronary Artery Disease/immunology* Diet, Atherogenic Endothelium, Vascular/immunology Humans Macrophages/immunology Mice Mice, Knockout Mice, Transgenic Monocytes/immunology*
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T-Lymphocytes/immunology* Tunica Intima/immunology
Arterioscler Thromb. 1992 Jun;12(6):745-53.
55.
Increased susceptibility to activation and increased uptake of low density lipoprotein by cholesterol-loaded macrophages.
Oiknine J, Aviram M.
Lipid Research Laboratory, Rambam Medical Center, Haifa, Israel.
Abstract
Inflammation is associated with macrophage activation, and this process has been shown to occur during atherogenesis. Macrophages (J774A.1) that were activated with either lipopolysaccharide (LPS), zymosan, or phorbol ester demonstrated a 30-35% increased uptake and degradation of low density lipoprotein (LDL) in comparison with nonactivated cells. This phenomenon was also shown for LDL cellular binding, and it resulted in macrophage cholesterol accumulation, as evidenced by cholesterol mass determination and flow cell cytometric analysis. Enhanced uptake of LDL was also obtained with two other types of macrophages: mouse peritoneal macrophages and human monocyte-derived macrophages. In LPS-stimulated macrophages, high density lipoprotein-mediated cholesterol efflux was not different from that shown in nonstimulated cells. Cellular cholesterol synthesis, however, was increased by 25% in the activated macrophages. Macrophage activation, measured as cellular procoagulant activity, was higher in cholesterol-loaded than in nonloaded cells. On stimulation of cholesterolloaded macrophages, cellular uptake and degradation of LDL were increased by 3.3-fold in comparison with nonactivated cholesterol-loaded cells. Human monocyte-derived macrophages from hypercholesterolemic patients were found to contain 52% more cholesterol mass than macrophages derived from normal healthy donors. These cells demonstrated increased activation (twofold) in response to LPS stimulation and also showed 25% enhanced cellular degradation of LDL. We conclude that activation of macrophages during atherogenesis can lead to foam cell formation, and this mechanism is probably operative in hypercholesterolemic patients.

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Animals Cell Line Cholesterol/metabolism Cholesterol/pharmacology* Humans Hypercholesterolemia/blood Lipopolysaccharides Lipoproteins, LDL/metabolism* Macrophage Activation/drug effects* Macrophages/drug effects Macrophages/physiology* Mice Receptors, LDL/metabolism Salmonella typhimurium Tetradecanoylphorbol Acetate/pharmacology Zymosan/pharmacology Substances Lipopolysaccharides Lipoproteins, LDL Receptors, LDL Tetradecanoylphorbol Acetate Cholesterol Zymosan
14-10-2012

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