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Acute phase reaction

The term acute phase response summarizes a number of very complex endocrine and metabolic
or neurological changes observed in an organism, either locally or systemically, a short time after
injuries or the onset of infections, immunological reactions, and inflammatory processes (see
also: Neuroimmune network). Each form of injury or tissue disorder that precipitates an
inflammatory response inevitably also causes an acute phase reaction (see also: inflammation,
wound healing).
An acute phase reaction is characterized, among other things, by fever, and an increase in the
numbers of peripheral leukocytes, in particular an increase in the numbers of circulating
neutrophils and their precursors. At the same time one observes cellular and biochemical
alterations, in particular the coordinated synthesis of so-called acute phase proteins (APP) or
acute phase reactants (APR) by hepatocytes in the liver (Ruminy et al, 2001).
The acute phase reaction is initiated and mediated by a number of cytokines with inflammatory
activities secreted by a variety of cell types (polymorphonuclear leukocytes, fibroblasts,
endothelial cells, monocytes, lymphocytes etc.). The cascades of inflammatory cytokines in
different tissues represent amplification and regulatory pathways controlling the development of
acute phase responses in vivo. Therefore, this reaction is a direct consequence of the biological
activities of an organism's own mediator substances and not the result of intrinsic properties of
the infectious and/or inflammatory agents per se.

Regulation of acute phase reactions and Synthesis of acute phase proteins.

Inflammatory cytokines such as IL6, IL1, TNF, and others such as TGF, IFN, and LIF are produced
by inflammatory cells. They induce local and systemic reactions. Among other things these
mediators are involved in cell activation of leukocytes, fibroblasts, endothelial cells, and smooth
muscle cells, inducing the synthesis of further cytokines. These mediators also have direct actions in
hepatocytes of the liver. Activities are enhanced indirectly by activation of the pituitary/adrenal
gland axis, which involves synthesis of ACTH and subsequent production of cortisol. Cortisol can
enhance expression of IL6 receptors in liver cells and thus promotes IL6 mediated synthesis of acute
phase proteins.
Negative regulatory loops can involve inhibition of synthesis of IL6, IL1, and TNF by cortisol and
inhibition of the synthesis of IL1 and TNF in monocytes by IL6. Of all mediators participating in the
induction and regulation of acute phase protein synthesis IL6 appears to induce the broadest
spectrum of acute phase proteins whereas IL1 and TNF only induce the synthesis of subsets of these
proteins.

The main mediator of the acute phase reaction is IL6, which, in turn, is regulated by IL1. In
cultures of hepatocytes IL6 induces a spectrum of biochemical alterations, which more or less
resemble the patterns observed also in the serum during an acute phase reaction in vivo. Like
IL6, LIF and IL11 also induce an almost complete spectrum of physiological changes. A much
more restricted pattern of alterations is found with IL1 and TNF with each of them showing
almost identical activities. Some acute phase proteins are induced also by CNTF (ciliary
neurotrophic factor). Another factor stimulating hepatocytes and inducing hepatic synthesis of
acute phase proteins is CT-1.
Type, duration and degree of cellular activities and changes in these activities are influenced by
the doses and the combinations of the different cytokines and also by the order in which
individual factors act upon a particular target cell.
A variety of low molecular weight substances normally acting on the cells also play a major role
in the sequence of events. Glucocorticoids, for example, are of particular importance for the
progression of the acute phase reaction because their synthesis can be influenced by a number of
cytokines, and they also, in turn, influence the synthesis of cytokines. In hypophysectomized
individuals one observes a pronounced reduction of the synthesis of acute phase proteins (see
also: inflammation, Systemic inflammatory response syndrome).
REFERENCES: Akira S and Kishimoto T IL6 and NF-IL6 in acute-phase response and viral
infection. Immunological Reviews 127: 25-50 (1992); Andus T et al Effects of cytokines on the
liver. Hepatology 13: 364-375 (1991); Baumann H and Gauldie J The acute phase response.
Immunology Today 15: 74-80 (1994); Heinrich PC et al Interleukin 6 and the acute phase
response. Biochemical Journal Supplement 269: 51-66 (1990); Kushner I et al The acute phase
response is mediated by heterogeneous mechanisms. Annals of the New York Academy of
Sciences 557: 19-30 (1988); Kushner I et al The acute phase response: (an overview). Methods
in Enzymology 163: 373-383 (1988); Pepys MB (editor) Acute phase proteins and the acute
phase response. Springer, Heidelberg, 1989); Ruminy P et al Gene transcription in hepatocytes
during the acute phase of a systemic inflammation: from transcription factors to target genes.
Inflammation Research 50(8): 383-390 (2001); Sehgal PB et al Regulation of the acute phase
and immune responses: interleukin-6. Annals of the New York Academy of Sciences Vol. 557
(1989); Thompson D et al Insulin modulation of acute phase protein production in a human
hepatoma cell line. Cytokine 3: 619-626 (1991)

Acute phase reaction

The following COPE entries contain this entry term or one of its hypertext
synonyms:
Acute phase protein inducing factor, Acute phase proteins, Acute phase response,
acute phase serum amyloid A, Alpha-2-Macroglobulin, APP, APPIF, APR, A-SAA, CD55,
CD59, Cytokines, CytokineTopics, drosocin, ETAF, Fetuin-B, Fetuin, gadd153, GM-CSF,
guanylin, Haptoglobin, HSF-2, HSF-3, IL11, IL1, IL6, IL6RE, inflammation, Inhibin-beta-E,
ITI, LEM, LIF, M20 interleukin-1 inhibitor, MAF, Neuroimmune network, NF-kappa-B,
Pentoxifylline, PF4, PIF, receptor shedding, SAA, Shwartzman phenomenon, SP,
Systemic inflammatory response syndrome, Thrombospondin-1.