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Contents lists available at ScienceDirect

Seminars in Immunology
journal homepage:www.elsevier.com/locate/y
smim

Interleukin-1 in innate inflammation, autophagy and immunity

a

Leo A.B. Joosten , Mihai G. Netea , Charles A. Dinarello

a,b,

Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The

b
Netherlands Department of Medicine, University of Colorado Denver, Aurora, CO,
USA

article inf
o
Keywords:
Interleuki
n-1
Innate
inflamma
tion
Autopha
gy
Caspase-1independent

abstract
Although IL-1 is the master inflammatory cytokine in the IL-1 family, after more
than ten years of continuous breeding, mice deficient in IL-1 exhibit no
spontaneous disease. Therefore, one concludes that IL-1 is not needed for
homeostasis. However, IL-1 -deficient mice are protected against local and
systemic inflammation due to live infections, autoimmune processes, tumor
metastasis and even chemical carcinogenesis. Based on a large number of
preclinical studies, blocking IL-1 activity in humans with a broad spectrum of
inflammatory conditions has reduced disease severity and for many, has lifted
the burden of disease. Rare and common diseases are controlled by blocking
IL-1 . Immunologically, IL-1 is a natural adjuvant for responses to antigen. Alone,
IL-1 is not a growth factor for lymphocytes; rather in antigen activated
immunocompetent cells, blocking IL-1 reduces IL-17 production. IL-1 markedly
increases in the expansion of naive and memory CD4T cells in response to
challenge with their cognate antigen. The response occurs when only specific
CD4T cells respond to IL-1 and not to IL-6 or CD-28. A role for autophagy in
production of IL-1 has emerged with deletion of the autophagy gene ATG16L1.
Macrophages from ATG16L1-deficient mice produce higher levels of IL-1 after
stimulation with TLR4 ligands via a mechanism of caspase-1 activation. The
implications for increased IL-1 release in persons with defective autophagy may
have clinical importance for disease.
2013 Published by Elsevier Ltd.

gastroin-testinal tract, each contain pre-formed IL-1

, IL-18 and IL-33 as
1. Interleukin-1 and innate inflammation
Independent of the type of organism or its
products, the innate response is actually a form of
acute inflammation in which the host initiates its
defenses by releasing phagocytic cells from bone
marrow reserves and facilitating their infiltration
into the area of the invading microbe in an attempt
limit infection and kill-off the invader. Systemically,
the liver increases the synthesis of acute phase
proteins, including anti-proteases. Even in
humans, in most cases this process protects the
subject without the use of antibiotics. For example,
a break in the skin allows bacteria to gain access
to the dermis and subsequent inflammation
provides acti-vation of complement, the release of
pre-formed cytokines from keratinocytes, an
increase in vascular wall adhesions molecules and
the extravasation of neutrophils. This response
has functioned to battle against invaders for
millions of years and can be traced back to fruit
flies. The skin, lung and intestinal tract each
provide a first line of defense against microbial
invasion and the lining cells, whether keratinocytes
of the skin, the alveolar epithelial cells of the
pulmonary tree or the epithelial cells of the entire

Corresponding author at: Department of Medicine,

University of Colorado Den-ver, Aurora, CO, USA. Tel.: +1 303
315 3558; fax: +1 303 315 8054.
E-mail address: cdinare333@aol.com (C.A. Dinarello).
1044-5323/$ see front matter 2013
Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.smim.2013.10.01
8

well as the members of the IL-36 subfamily. Since

these members of the IL-1 family are each preformed in these cells, their release is a
consequence of injury and is immediate.
Therefore, they are termed alarmins as they alert
the host to initiate the response.
There are other alarmins from the lining cells
that par-ticipate in defense, for example,
defensins, which are directly anti-microbial. Each
of the constitutively present IL-1 family mem-bers
in lining cells is present as a precursor. In the case
of IL-1 , the precursor is fully active; in the case of
the other members, the pre-cursors are weakly
active at first but are converted to more active
cytokines upon the infiltration of neutrophils and
processing by extracellular neutrophil proteases. In
the end, the infection is con-tained, the invading

microorganism is eliminated and tissue begins its

process of repair. Following the cloning of the
mouse IL-1 recep-tor [1], the cytosolic domain of
the IL-1 receptor was found to be homologous to
Toll of the fruit fly [2]. Moreover, at the same time,
the TIR domain for IL-1 signaling was shown by
Heguy to be required for IL-1 signaling [3]. Toll had
been initially studied since its discovery in 1985
because of its central role in establishing dor-sal
ventral polarity in Drosophila. Only since 1996 was
Toll linked to survival in fruit flies infected with fungi
[4]. However, it had already been reported, back in
1988, that a member of the IL-1/TLR family, human
IL-1 , protected mice from lethal Pseudomonas
infection [5]. As noted above, the TIR domain is
essential for both IL-1 recep-tor family and TLR
family signaling; a mutation in the TIR domain
severely impairs responses to IL-1 family ligands
as well to a large

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number of microbial products [6]. The TIR domain

binds MyD88, itself a TIR domain-containing
protein, through TIR/TIR interactions triggering a
cascade of kinases that propagate the IL-1 signal
and result in transcription of a large number of
genes, the majority of which code for other
cytokines, chemokines and a host of inflam-matory
mediators. Of these is IL-1 itself and other
members of the IL-1 family such as IL-36 and IL18.
The innate immune response regulates to the
acquired immune response. The late Charles
Janeway proposed that the innate response
assists the host in mounting an acquired immune
response. This relationship between a non-specific
cytokine pro-viding help for a specific response to
a microbial antigen is simply the adjuvant property
of some cytokines. The adjuvant property of some
cytokines functions by upregulating lymphocyte
growth factors such as IL-2, IL-4 and IL-6 or
lymphocyte receptors result-ing in expansion of
lymphocyte clones, which will either rid the host of
the invading microorganism with neutralizing
antibodies or in generation of cytotoxic T-cells to
eliminate viral infections. In 1979, purified human
IL-1 , a non-specific macrophage product, was
shown to augment the T-cell response to specific
antigen [7]. It was nearly 20 years later that TLR
were identified as inducing IL-1 from monocytes.

1.1. IL-1, the master cytokine in the IL-1 family

More than any other member of the IL-1 family,
IL-1 has been the focus of most studies. IL-1 is a
highly inflammatory cytokine, particularly in
humans, as reviewed in [8]. IL-1 and IL-1 bind to
the same IL-1R1 and trigger a proinflammatory
signal. The inter-est in IL-1 is also due, in part, to it
being a secreted cytokine from macrophages and
to the importance of the macrophage in antigen
presentation before the era of dendritic cells. The
inac-tive IL-1 precursor is converted into an active
cytokine by the intracellular cysteine protease
caspase-1. In particular, persons with activating
mutations in one of the key genes that control the
activation of caspase-1 can develop lifethreatening systemic inflammation, which is

reversed by either blocking the IL-1 recep-tor or

through the use of a neutralizing antibody to IL-1 .
Other chronic inflammatory diseases are mediated
by IL-1 , as neu-tralizing antibodies have been
used to treat a broad spectrum of diseases. The IL1 -mediated illnesses fall into the category of
autoinflammatory diseases, which are to be
distinguished from the classic autoimmune
diseases. Although inflammation is com-mon to
both autoinflammatory and autoimmune diseases,
in the case of IL-1-mediated disease, there is no
evidence for role of adap-tive immunity in its
induction.

1.2. IL-1 is an inducible cytokine

Unlike IL-1 , the IL-1 precursor is not present in
health. Also unlike IL-1 , IL-1 is primarily a product
of monocytes, macrophages and dendritic cells
(DC) as well as B-lymphocytes and NK cells. In
health, circulating human blood monocytes or bone
marrow cells do not constitutively express mRNA
for IL-1 . Endothelial cells, skin keratinocytes,
fibroblasts and epithelial cells contain constitutive
IL-1 and constitutive IL-33 as precursors as well as
mRNA but these cells do not express IL-1 mRNA
even upon stimulation with TLR ligands. Melanoma
cells do express IL-1 as a precursor and the more
aggressive and metastatic the melanoma, the
greater the likelihood of active caspase-1 and IL-1
secretion [9]. In the bone marrow neutrophil
precursors, IL-1 gene expres-sion is inducible but
mature neutrophils in the circulation no longer
produce IL-1 . Neutrophil IL-1 plays a pathological
role in the severe inflammation of mice with a
mutant form of the phosphatase SHP1 [10].
Several malignant tumors do express IL-1 as part
of their neoplastic nature, particularly acute
myelogenous leukemia,

melanoma, multiple myeloma and juvenile

myelogenous leukemia, each of which exhibit
constitutive expression of IL-1 . Unlike most
cytokine promoters, IL-1 regulatory regions are
distributed over several thousand base pairs
upstream from the transcriptional start site. In
addition to a cAMP response element, there are
NF- B-like and activating protein-1 (AP-1) sites. IL1 gene regulation has been reviewed in detail [11].
Although steady-state mRNA levels for IL-1 may
be present, there is distinct dissociation between
tran-scription and translation of the IL-1 precursor.
Non-TLR ligands such as the complement
component C5a, hypoxia, adherence to surfaces,
or clotting of blood induce the synthesis of large
amounts of IL-1 mRNA in monocytic cells without
significant translation into the IL-1 protein. In these
cells, the IL-1 mRNA assembles into large
polyribosomes, but there is no significant
elongation of the peptide [12]. This failure to
complete the translation into IL-1 protein may be
due to the instability element present in the coding
region. This instability region is also found in IL-18
and IL-37 and appears to limit the mRNA of these
cytokines [13]. However, com-pletion of translation
of the mRNA into the respective cytokines can be
accomplished by adding low concentrations of TLR
ligands or IL-1 itself to the primed monocytes
[14].
1.3. Processing and secretion of IL-1 via the
caspase-1
Nearly all microbial products induce IL-1 via
TLR activation; in addition, IL-1 (either IL-1 or IL1 ) induces itself both in vivo and in monocytes in
vitro [15]. Other studies supporting this con-cept of
IL-1-induced IL-1 have been reported [1619].
Regardless of the stimulus, processing and
secretion of IL-1 requires con-version of
procaspase-1 to active caspase-1, although in
some studies processing of the IL-1 precursor is
caspase-1 independent [20]. The activation to
active caspase-1 is dependent on a com-plex of
intracellular proteins termed the inflammasome

by the late Tschopp [21,22]. The critical component

of the inflammasome is NLRP3. NLRP3 is also
termed cryopyrin since the gene was ini-tially
discovered in patients with familial cold autoinflammatory syndrome, a genetic disease
characterized by constitutional symp-toms, fevers
and elevated acute phase proteins following
exposure to cold [23]. As monocytes exit the bone
marrow, they circulate in the blood stream for
approximately three days. In the absence of
disease, it is likely that these cells do not enter
tissues but are destroyed in the spleen or undergo
apoptosis. There is no dearth of reports that
circulating human blood monocytes release
processed IL-1 upon stimulation starting 4 h after
stimulation with TLR agonists and continues to
release the cytokine during the follow-ing 2040 h.
Following LPS, IL-1 mRNA levels rise rapidly within
15 min but begin to decline after 4 h due to the
short half-life of their mRNA or the action of micro
RNA. In contrast, using IL-1 itself as a stimulant,
IL-1 mRNA levels are sustained for over 24 h [14].
Raising intracellular cAMP levels with histamine
enhances IL-1-induced IL-1 gene expression and
protein synthesis. Monocytes of patients with
autoinflammatory diseases such as CAPS and
HIDS release IL-1 even without TLR stimulation
during a 24 h incubation [24,25]. When obtained
from the venous blood of healthy subjects, human
blood monocytes contain active caspase-1. Active
caspase-1, as determined by its cleavage into the
active dimer, is present even in the absence of
stimulation [26]. Active caspase-1 present in
freshly obtained monocytes is nevertheless
dependent on the presence of the key components
of the inflammasome, namely ASC and NLRP3
[26]. However, during subsequent incubation,
extra-cellular levels of ATP increase in the
supernatant as IL-1 also increases and inhibition of
ATP by oxidized ATP reduces the secre-tion of IL-1
[26]. The inhibition of IL-1 secretion by oxidized
ATP is consistent with the role of the P2X7
receptor, which binds ATP and opens the
potassium channel for release of intracellular
potassium. The presence of active caspase-1 in
circulating blood

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monocytes suggests that the rate limiting step in

the processing and release of IL-1 is at the level of
gene expression. However, upon differentiation of
the same blood monocytes into macrophages in
vitro, TLR-induced IL-1 release requires activation
of caspase-1 by exogenous ATP [26]. The
assembly of the inflammasome com-ponents with
inactive pro-caspase-1 takes place following a fall
in intracellular potassium triggered by ATP binding
to the P2X7 receptor. ATP activation of the P2X7
receptor opens the potassium channel, and
simultaneously, as potassium levels fall, caspase-1
is activated by the inflammasome [2731]. Without
exogenous ATP, there is little or no processing of
the IL-1 precursor in differ-entiated monocytederived macrophages. Alveolar macrophages
obtained from the lungs of healthy human also do
not release IL-1 with LPS stimulation unless
exogenous ATP is added [26]. In addi-tion to ATP
activation of P2X7, activation of IL-1 processing
can also take place with a cathelicidin-derived

peptide termed LL37, which is released from

neutrophils [31]. The cleavage of the IL-1 precursor
by active caspase-1 can take place in the
specialized secretory lysosomes or in the
cytoplasm. However, more than one pathway
seems available for processed IL-1 to exit the cell.
These include by exocytosis of the secretory
lysosomes [27,28], shedding of plasma membrane
microvesicles, direct release via transporters or
multivesicular bodies containing exosomes [32]. In
general, the release of processed IL-1 takes place
before there is significant release of lactate
dehydrogenase [33], although in vitro cell death
eventually takes place. Pyroptosis is a caspase-1dependent form of cell death and is induced by
certain bacteria using Ipaf, a mem-ber of the NLR
family of intracellular receptors [34]. An increase in
intracellular calcium is also required for the mature
IL-1 to exit the cell and is phospholipase C
dependent [28].

1.4. Gain of function mutation in cryopyrin

Diseases associated with single amino acid
activating mutations in cryopyrin are termed
Cryopyrin-Associated
Periodic
Syndromes
(CAPS). In monocytes from patients with CAPS,
activation of caspase-1 occurs without a
requirement for a rapid fall in the level of
intracellular potassium [19]. Therefore, mutated
cryopyrin allows for the assembly of the complex
of interacting proteins in the presence of normal
intracellular levels of potassium. Although often
studied using LPS-induced synthesis of the IL-1
precur-sor [35], it is unlikely that LPS plays a role
in auto-inflammatory diseases. On the other hand,
spontaneous secretion of IL- from monocytes of
patients is due to endogenous IL-1 stimulation. In
patients with CAPS, there is a decrease in steady
state levels of pro-caspase-1 mRNA with IL-1Ra
treatment [16], suggesting that IL-1 stimulates its
own production and processing. Thus, in any
disease process that includes an increase in the
steady state levels of pro-caspase-1 mRNA,
components of the inflammasome or the IL-1
precursor explain the auto-inflammatory nature of
the disease. Type 2 diabetes appears to be an
example of an auto-inflammatory disease where
glucose induces IL-1 production from the insulinproducing beta cell and IL-1 induces the beta cell
to produce its own IL-1 [36].

1.5. Polymorphisms in P2X7 and

the activation of the inflammasome
Patients
with
classic
auto-inflammatory
diseases such as FMF or CAPS have nearly
identical clinical parameters, secrete more IL-1
and respond dramatically to IL-1 receptor blockade
yet have no mutation in NALP3. It is therefore
possible that mutations in P2X7 itself or regulation
of the other genes controlling potassium channels
[37] may account for dysfunctional secretion of IL1 . For example, monocytes from patients with
rheumatoid arthritis are more sensitive to release
of IL-1 following ATP activation of

the P2X7 receptor compared to monocytes from

healthy controls [38]. However, monocytes from
subjects with a P2X7 Glu496Ala loss-of-function
polymorphism secrete significantly less IL-1 [39].
Monocytes from subjects homozygous for this
polymorphism also released significantly less IL-18
[40]. Another P2X7 receptor polymorphism is
associated with increased mortality in patients
undergoing allogenic stem cell transplantation [41].
Bacteremia was documented in 68% of patients
with this polymorphism com-pared to 18% in wildtype control patients [41]. In mice deficient in P2X7
receptors, inflammation, pain and IL-1 -mediated
IL-6 production are markedly reduced [42]. In
addition to a fall in intra-cellular potassium, ATP
triggers formation of peroxynitrite, which is required
for caspase-1 activation since peroxynitrite
scavengers prevent IL-1 secretion [43]. Pannexin1, a mammalian protein that functions as a
hemichannel for the uptake of dyes, is required for
caspase-1 processing and release of IL-1 via the
P2X7 receptor [44]. Pannexin-1 can also function
for LPS-induced IL-1 synthesis in the absence of
TLR4 [45]. P2X7 receptor activity is also regulated
by regeneration and tolerance factor [46].

1.6. Reactive oxygen species and IL-1 processing

Is there a role for reactive oxygen species
(ROS) in the activa-tion of the IL-1 inflammasome?
It was reported that uric acid crystals added to
human monocytes result in the generation of ROS,
which bind to and activate NLRP3 with subsequent
secretion of IL-1 [47]. However, mice deficient in
ROS production exhibit a proinflammatory
phenotype [48]. Humans with chronic granulomatous disease (CGD) due to mutations in p47phox cannot generate ROS and are severely
affected by inflammatory gran-uloma. Uric acid
crystal activation of primary monocytes from
persons with CGD produced four-fold higher levels
of IL-1 com-pared to monocytes from unaffected
persons [49]. In contrast to previous studies [47],
the small molecule ROS inhibitor dipheny-lene
iodonium, which reduces the production of IL-1 ,
does so due to inhibition of IL- gene expression
rather than decreased caspase-1 activation [49].
Another study identified phagocyte oxi-dase
defective monocytes from CGD patients as a
source of elevated IL-1 [50]. These findings
support the concept that ROS likely dampens
inflammasome activation and may explain the
presence
of
an
inflammatory
phenotype
characterized by granulomas and inflammatory
bowel disease occurring in CGD patients. In fact,
patients with CGD-related inflammatory bowel
disease improve upon IL-1 receptor blocking
therapy [51].

1.7. Effects in mice deficient in IL-1

After ten years of continuous breeding, mice
deficient in IL-1 exhibit no spontaneous disease.
However, upon challenge, IL-1 - deficient mice
exhibit specific differences from their wild-type
controls. The most dramatic is the response to
local inflammation induced by a subcutaneous
injection of an irritant. Within the first 24 h, IL-1
-deficient mice do not manifest an acute phase
response, do not develop anorexia, have no
circulating IL-6 and no fever [52,53]. These
findings are consistent with those reported in the
same model using anti-IL-1R type I antibodies in

wild-type mice [52,53]. IL-1 -deficient mice also

have reduced inflammation due to zymosaninduced peritonitis [52,54]. In contrast, IL-1
-deficient mice have elevated febrile responses to
LPS, IL-1 or IL-1 com-pared to wild-type mice [55].
Nevertheless, IL-1 -deficient mice injected with
LPS have little or no expression of leptin mRNA or

protein [56]. Mice deficient in IL-1 were compared

to mice deficient in IL-1 after exposure to chemical
carcinogens [57]. In IL-1 -deficient mice, tumors
developed slower or did not develop in some mice.
A deficiency in IL-1 , on the other hand, did not
impair tumor development compared to wild-type
mice injected

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with the same carcinogen. In IL-1Ra-deficient

mice, tumor devel-opment was the most rapid. A
leukocyte infiltrate was found at the site of
carcinogen injection. The neutrophilic infiltrate was
almost absent in IL-1 -deficient mice, whereas in
IL-1Ra-deficient mice, a dense neutrophilic
infiltrate was observed. In wild-type mice, the
leukocytic infiltrate was sparse and the infiltrate
that was observed in IL-1 -deficient mice was
similar to that of control mice. These findings may
reflect the fact that IL-1 is secreted into the
microenvironment resulting in the emigration of
monocytes and neutrophils, whereas IL-1
remaining cell-associated is less likely to affect the
microenvironment.

1.8. IL-1 and joint diseases

A hallmark of rheumatoid arthritis (RA) is the
progressive destruction of cartilage and bone due
to the chronic inflamma-tion. Histopathological
features of RA synovial tissue encompass
infiltration by macrophages and T cells, synovial
lining hyper-plasia, neoangiogenesis and pannus
formation. Proinflammatory cytokines as TNF and
IL-1 are considered key mediators in the joint
inflammation and in the destruction of cartilage
and bone in patients with RA [5860]. It has been
repeatedly demonstrated that IL-1 is involved in
the joint pathology found in chronically inflamed
joints [6163].

1.9. Arthritogenicity of IL-1

It is now generally accepted that arthritis can
be induced in mice by IL-1 . This was
demonstrated by local injection of IL-1 or
intraarticular overexpression by local gene transfer
of the cytokine. One single injection of IL-1 in knee
joints of mice results in disturbance of cartilage
proteoglycan synthesis and influx of inflammatory
cells [64,65]. Using IL-1 gene transfer, prolonged
exposure to IL-1 in rabbit or murine knee joints
results in chronic destructive arthritis that
resembles most features of rheumatoid arthritis. As
shown in Fig. 1, IL-1 deficient mice are protected
against loss of proteoglycan compared to TNF
deficient mice. Using gene transfer, IL-1 induces
greater cartilage destruction in vivo. Small
amounts of IL-1 are sufficient to cause
chondrocyte proteoglycan synthesis inhibition,
whereas 1001000 fold higher doses of TNF are
required to obtain the same effect [66]. How-ever,
when local TNF is locally overexpressed for long
periods using adenoviral constructs coding for
mouse TNF , mild cartilage destruction is
observed.

1.10. Role of IL-1 in models of arthritis

The above data illustrate the potency of IL-1 in
single mediator systems, however the exact role of
IL-1 remains to be identified in accepted models of
arthritis, using antibodies, IL-1 receptor antag-onist
(IL-1Ra) or IL-1 gene deficient mice. The most
widely used

model of experimental arthritis is the murine type II

collagen-induced arthritis (CIA). It has been shown
that IL-1 and TNF play important roles in CIA, as
both cytokines accelerate disease onset and
severity when applied locally [67]. Kinetic studies
were per-formed to compare TNF and IL-1
blocking in CIA, starting before onset, shortly after
and at late full-blown arthritis. Neutralizing antiTNF antibodies or soluble TNF-receptor fusion
protein ame-liorate the disease expression only
when the treatment was started directly before or
shortly after onset of the disease. Mice with established CIA showed no suppression of disease
activity when treated with anti-TNF therapy. In
contrast to TNF blockade, anti-IL-1 antibodies or
anakinra (administrated by osmotic minipumps)
were highly suppressive both during onset of
murine CIA and in established full-blown arthritis.
Interestingly, it was demonstrated, using specific
antibodies that IL-1 was the dominant isoform of
IL-1 [61,62]. Detailed analysis of joint pathology
revealed that anti-IL-1 or anakinra treatment of
established CIA prevented cartilage and bone
destruction entirely [61,62]. The strong IL-1
dependency of murine CIA was further
demonstrated by elegant studies using IL-1
knockout mice, caspase-1 inhibitors and caspase1 gene defi-cient mice [68,69]. Similar approaches
were performed to study the role of TNF in murine
CIA using TNF-receptor type I (TNFRI) gene
deficient mice in the DBA-1 background. It was
shown that TNFRI knockout mice develop CIA with
a lower incidence and disease activity. However,
when a joint was afflicted the arthri-tis progressed
in a similar way as the wild type mice [70]. These

data are in line with previous findings that TNF is

important in early stages of murine CIA. The above
data suggests that not all IL-1 is driven by TNF ,
since IL-1 blocking was far more potent as
compared to TNF neutralization, in particular at
late stages of murine CIA. It can be argued that the
TNF inhibitors were not sufficient to block all TNF .
However, it was elegantly shown that induction of
CIA in TNF deficient mice in C57/Black6
background resulted in severe disease in 54% of
the animals, indicating that severe disease could
proceed even in the complete absence of TNF
[71].

IL-1 is also crucial during flares of arthritis. In

the model of murine Streptococcus pyogenes cell
wall (SCW) arthritis, flares can be induced at sites
of smoldering arthritis by rechallenge with small
amounts of SCW fragments [72]. Interestingly, IL-1
did not play a role in the acute phase of SCWinduced arthritis in contrast to TNF . It was found
that after each reactivation of the arthritis, three in
total, the induction of joint swelling was TNF
dependent, although after the third local injection of
SCW fragment the effect of TNF blockade or TNF
deficiency was limited. The chronic cellular infiltrate remains and cartilage destruction is not
significantly reduced in TNF knockout mice or mice
treated with soluble TNFR-Fc pro-tein [72]. In
contrast, major protection against cartilage and
bone destruction was seen in mice treated with
anti-IL-1 or in IL-1 gene deficient mice. In addition,
the chronic synovial infiltrate was profoundly
reduced in the IL-1 deficient mice. This does
suggest

Fig. 1. (A) Chronic SCW-induced arthritis in WT mice. Day 28 of arthritis, note the severe cartilage visualized by loss of Safranin O
staining (red). (B) Almost complete protection in IL-1 deficient mice. (C) TNF deficient mice, similar cartilage destruction as seen in
WT mice. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

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that the repeated flare reactions make the

inflammatory process in the synovial membrane
IL-1 -dependent phenomenon.
Consistent with these observations are data in
which IL-1 was deleted in a TNF -mediated joint
inflammation. When human TNF transgenic mice
were crossed with IL-1 deficient mice it became
clear that synovial inflammation was not affected
but the cartilage and bone destruction was almost
prevented [63]. In gouty arthritis has been
repeatedly demonstrated that IL-1 is the pivotal
mediator that causes the joint inflammation.
Recent studies with anakinra or neutralizing
antibodies
directed
against
IL-1
showed
impressive amelioration of this crystal-induced joint
pathology [73] [74]. Gouty arthritis is seen as a

classical IL-1-mediated joint disease and it is well

known that caspase-1 is needed for processing of
pro-IL-1 . However in models of experimental gouty
arthritis it is demonstrated that caspase-1 is not
needed for local IL-1 pro-duction. It reveals that
serine proteases derived from neutrophils, such as
proteinase 3 (PR3) can process pro-IL-1 to
bioactive IL-1 [75]. Not only in gouty arthritis, but
also in other models experi-mental of arthritis this
caspase-1-independent
phenomenon
was
demonstrated, as discussed in the next section
[76,77].
1.11. Non-caspase-1 processing of IL-1
Non-caspase-1 mechanisms also exist to
generate active forms of IL-1 . For example, sterile

inflammation induces fever, elevated IL-6 and

increased production of hepatic acute phase
proteins. These responses are absent in mice
deficient in IL-1 but present in mice deficient in
caspase-1 [52,76]. Sterile inflammation is often
associated with neutrophilic infiltration and
neutrophils produce IL-1 . Because neutrophils are
short-lived cells dying within hours upon
emigration, release of the IL-1 precursor from
intracellu-lar stores is not unexpected. Processing
of the IL-1 precursor extracellularly into an active
cytokine has been reported for the common
neutrophil
protease,
proteinase-3
[76,78].
Proteinase-3 also contributes to the processing of
IL-18 [79]. Other proteases such as elastase,
matrix metalloprotease 9 and granzyme A process
the IL-1 precursor extracellularly. In addition, a
mast cell chy-mase generates active IL-1 . Mice
with a targeted IKK deletion in myeloid cells are
more susceptible to LPS-induced shock than control mice [17] and markedly elevated levels of IL-1
are found in the circulation associated with a
prominent neutrophilia [17]. The elevated levels of
IL-1 are lethal since blockade with IL-1Ra pro-tects
these mice from death. The source of the IL-1 in
these mice is the neutrophil. When incubated with
proteinase-3, cleavage of the IL-1 precursor is
observed yielding molecular weights of 25,000 and
15,000 Da [17]. Because the cleavage of the IL-1
precursor by proteinase-3, elastase and cathepsin
G are within 3 amino acids of the caspase-1
cleavage site, the products of the non-caspase-1
cleavage are biologically active [76,78]. Therefore,
in inflammatory conditions such as urate crystal
arthritis, which is characterized by a prominent
neutrophilic infiltration, proteinase-3 cleavage of
extracellular IL-1 precursor likely takes place [75].
Mice deficient in caspase-1 are not protected
against urate-induced inflamma-tion. Although IL1Ra is effective in treating gout, IL-1Ra would be
equally effective in any disease with extracellular
processing of the precursor [73,74,80]. The
importance of extracellular processing of the IL-1
precursor by serine proteases may explain, in part,
the anti-inflammatory properties of alpha-1antitrypsin [81].

2. Interleukin-1 and autophagy

Autophagy is an ancient process of recycling
cellular compo-nents, such as cytosolic organelles
and protein aggregates, through degradation
mediated by lysosomes. Autophagy is activated in
conditions of cell stress, hypoxia, starvation, or
growth factor depri-vation; it promotes cell survival
by generating free metabolites and

energy through degradation of the endogenous

cellular compo-nents [82]. However, in addition to
its role in the pathophysiology of cancer,
neurodegenerative diseases, or aging, autophagy
is also a modulator of inflammation [83]. A role for
autophagy in pro-duction of proinflammatory
cytokines, particularly of IL-1 has emerged with
deletion of ATG16L1. For example, macrophages
from ATG16L1-deficient mice produce higher levels
of IL-1 and IL-18 after stimulation with TLR4
ligands [84]. The data suggest that higher
activation of caspase-1 in the ATG16L1-deficient
mice accounts for the higher production level [84].
This observation was related the specific
degradation
of
the
IL-1
precursor
in
autophagosomes in mouse macrophages [85].
Additional studies in the ATG16L1-deficient mice
point towards a regulatory effect of autophagy on
caspase-1 activation through modulation of the
NLRP3 inflammasome [47,86,87]. This role of
autophagy in the secretion of IL-1 was also
observed in human primary monocytes, in which
specific inhibition of autophagy leads to increased
pro-duction of IL-1 [88]. However, in the same cells
TNF production was decreased by autophagy
inhibition. These data suggest diver-gent effects of
autophagy on the production of these two
important proinflammatory cytokines. In mice, the
increase in IL-1 produc-tion is ascribed to
increased activation of the inflammasome but in
human cells, it is IL-1 mRNA transcription that is
elevated when autophagy was inhibited, whereas
no effects were observed on caspase-1 activation
[84,85,88]. Despite these differences between
mouse and human cells, the inhibition of
autophagy increases the production of IL-1 but not
TNF .
The modulation of inflammation by autophagy
in humans has been studied in Crohns disease.
Genome-wide association stud-ies in large cohorts
of Crohns disease patients have revealed that
genetic variants in two autophagy genes, ATG16L1
and IRGM result in increased susceptibility to the
disease. A non-synonymous polymorphism in
ATG16L1 on chromosome 2q37.1 and two
polymorphisms in IRGM on chromosome 5q33.1
were significantly associated with Crohns disease
risk [89,90]. Another study revealed a significant
association of Crohns disease suscep-tibility with
an intronic polymorphism in the autophagy gene
ULK1 [91]. Moreover, autophagy defects have
been reported in individ-uals bearing NOD2
mutations, and are consistent with the concept that
impaired bacterial clearance and increased
bacterial persis-tence are part of the pathogenesis
of Crohns disease [92]. The mechanism through
which polymorphisms in autophagy genes
influence susceptibility to Crohns disease appear
to involve IL-1 production. The ATG16L1 300Ala
risk allele was associated with elevated production
of IL-1 and IL-6; however, this finding was only
observed in cells stimulated with the NOD2 ligand
muramyl dipeptide (MDP). In contrast, the
expected levels of IL-1 and IL-6 were produced
upon stimulation with TLR2 and TLR4 ligands [93].
The increased production of IL-1 was associated
with an increase in the steady state levels of IL-1
mRNA rather than increased activation of the
inflammasome [93]. Studying the same polymorphism (ATG16L1 Thr300Ala) in human dendritic
cells, Cooney et al. reported defective NOD2induced, but not TLR-induced, autophagy and
antigen presentation [94]. Furthermore, effects of
this poly-morphism on antibacterial autophagy in

epithelial cells have been observed [95]. The

specific effect of the ATG16L1 polymorphism on
the NOD2 pathway, and not on TLR-induced
stimulation, is likely related to the fact NOD2 and
ATG16L1 form a protein complex that is essential
for NOD2-induced autophagosome formation [96].
Since the ATG16L1 Thr300Ala polymorphism
affects protein stabil-ity [97], defective induction of

autophagy and therefore enhanced IL-1 mRNA

transcription upon triggering of NOD2 may be due
to the presence of defective complex. In addition to
the induction of intracellular signals leading to the
production of cytokines, engage-ment of PRRs
such as NOD2 activates autophagy, a process in
which damaged organelles or long-lived proteins
are degraded.

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Fig. 2. Autophagy modulates Borrelia-induced IL-1 production. (A) Inhibition of autophagy results in enhanced production of
bioactive IL-1 PBMCs. (B) TNF production is not influenced by inhibition of autophagy. (C) Schematic overview how autophagy
controls Borrelia-induced IL-1 production.

Autophagy involves the sequestration of

dysfunctional pro-teins in a double-layered
membrane called autophagosome, which is
formed by the elongation of small membrane structures. The formation of this isolation membrane is
initiated by autophagy-related gene (Atg) 6 and
type III phosphatidylinositol 3-kinase (PI3K) [98].
The delivery of dysfunctional proteins to the
autophagosomes is regulated by autophagic
adaptors such as p62. This latter protein can bind
to the intracellular target as well as to the
microtubule-associated protein 1 light chain 3
(LC3), which associates with the autophagosome
after being processed [99]. Autophagosomes
mature through fusion with lysosomes, leading to
the breakdown of the protein content [100]. The
link between autophagy and the innate defense
mechanism has been made in several studies
describing the connection between dysfunctional

autophagy
and
autoinflammatory
diseases
[101,102]. It has been shown that the inhibition of
autophagy by chemical inhibitors of PI3 kinases
leads to an enhancement of extracellular IL-1 after
stimu-lation with bacterial wall components such as
LPS [88]. The fact that Borrelia burgdorferi is
recognized by the autophagy-inducing recep-tor
NOD2 leaded to the exploration of the role of
autophagy in host defense during infection with B.
burgdorferi. By stimulating human peripheral blood
mononuclear cells (PBMCs), it was demonstrated
that inhibition of autophagy increases IL-1 and IL-6
production after stimulation with Borrelia bacteria
(Fig. 2). The enhanced production was specific for
IL-1 and IL-6, while TNF production was
unchanged. The robust increased mRNA synthesis
of the proin-flammatory cytokines IL-1 and IL-6
indicated that autophagy

regulates Borrelia-induced IL-1 production on the

transcriptional level [103].

3. The IL-1 family and T helper responses

The IL-1 family plays a significant role in IFN
production, which is essential for the defense
against intracellular pathogens. On the other hand,
Th2 cells are characterized by the produc-tion of
ILIL-4 and are important in the host defense
against parasitic infections. For more than one
decade, the dichotomy between Th1 and Th2 has
been the focus of studies on differen-tiation of
CD4+ T-lymphocytes. More recently, Th17 helper

cells have been described and are characterized

by their production of IL-17. IL-17 plays a major
role in neutrophil recruitment and host defense
against extracellular bacteria and fungi. Th17 cells
produce a distinct cytokine profile, namely IL-17A,
IL-17F, IL-21 and IL-22. The cytokines produced by
Th17 cells, in addition to activating neutrophils, are
also crucial for non-immune cells, for example,
induction of defensins by IL-22 in epithelial cells
and keratinocytes, which are part of mucosal and
skin defenses. It has become apparent that Th17
responses
are
associated
with
chronic
inflammation and autoimmune diseases such as
multiple sclerosis, Type-1 diabetes, Crohns
disease and psoriasis. Furthermore, Th17
responses are fundamental for host defense
against many microor-ganisms, although they also
contribute to the inflammation during infection.

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Whereas IL-4 and IL-12 were the first cytokines

described as influencing Th cell differentiation,
cytokines of the IL-1 family also influence cytokine
differentiation. IL-18 was initially described as IFN
-inducing factor due to its strong stimulatory effect
on Th1/IFN responses [104]. It is now known that
IL-18 is, in fact, a crucial cytokine directing the
development of Th1 cells, and one role of IL-12 is
the induction of the expression of IL-18 receptors.
In contrast, binding of IL-33, another member of
the IL-1 family, to its ST2 receptor plays a role in
inducing Th2 responses [105], and it thus
appeared as if distinct members of the IL-1 family
of
cytokines
directed
Th1
versus
Th2
differentiation. Considering these effects of IL-18
and IL-33, it came as no surprise that IL-1, the
most well known member of the family,
participates in the function of Th cells.
Known for over 30 years that IL-1 enhances Tcell activation and recognition of antigen, one of
the early names of IL-1 was lym-phocyte activation
factor (LAF). The specificity of this response was
however not known. Although initially only IL-23,
IL-6, IL-21 and TGF were suggested to play a role
in the development of Th17 responses in mice,
there is no dearth of data that a more com-plex
picture exists. Thus, IL-1 , IL-6, TGF have been
reported to induce the development of Th17 cells,
while IL-23 has been reported to be important for
the maintenance of Th17 cells. The combination of
IL-23 and IL-1 induce the development of human
Th17 cells expressing IL-17A, IL-17F, IL-22, IL-26,
the chemokine CCL20, and transcription factor
ROR t [106]. Interestingly, these cells also
released IFN , displaying a phenotype common to
both Th17 and Th1 cells [106]. The strong capacity
of IL-1 to induce Th17 differentiation has been also
linked to its well-known capacity to induce the
release of prostaglandins, as reviewed in [107].
PGE2 induced by COX-2 is a stimulator of Th17
induction and inhibitors of cyclooxyugenase
decrease IL-17 production [108]. On the other
hand, engagement of the aryl hydrocarbon
receptor, a pathway demonstrated to be crucial for
the generation of Th17 cells, has been shown to
strongly induce IL-1 [109]. In addition to inducing
IL-17 production from the Th17 subset of
lymphocytes, IL-1 is required for the production of

IL-17 by NKT cells [110] and of IL-22 from NK

cells [111]. Thus, cytokines of the IL-1 family have
an important role in the differentiation of the Th
subsets, with IL-1 strongly inducing Th17
responses, IL-18 being crucial for the generation
of Th1 cells, while IL-33 being important in Th2
responses. Interest-ingly, reciprocal regulation
has been demonstrated between the various Th
subsets, with cytokines released by Th2 cells
inhibiting Th1 responses, while IFN release from
Th1 cells impairing both Th2 and Th17 responses.

Acknowledgement
These studies were supported by a grant from
the Dutch Arthri-tis Foundatiion (NR 10-1-303) to
LAJ Supported by NIH grant AI 15614 to CAD.
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Please cite this article in press as: Joosten LAB, et al. Interleukin-1 in innate inflammation, autophagy and immunity. Semin Immunol (2013),
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