Dinarello Charles 2009 Immunological AndInflammatory Functionsof The Interleukin-1 Family

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Immunological and
Inammatory Functions
of the Interleukin-1 Family
Charles A. Dinarello
Department of Medicine, Division of Infectious Diseases, University of Colorado Denver,
Aurora, Colorado 80045; email: cdinarello@mac.com
Annu. Rev. Immunol. 2009. 27:51950
Key Words
The Annual Review of Immunology is online at

immunol.annualreviews.org
cytokine, host defense, caspase-1, autoinammatory, inammasome
This articles doi:

10.1146/annurev.immunol.021908.132612
Abstract
c 2009 by Annual Reviews.

Copyright
All rights reserved
0732-0582/09/0423-0519$20.00
More than any other cytokine family, the interleukin (IL)-1 family is
closely linked to the innate immune response. This linkage became
evident upon the discovery that the cytoplasmic domain of the IL-1
receptor type I is highly homologous to the cytoplasmic domains of all
Toll-like receptors (TLRs). Thus, fundamental inammatory responses
such as the induction of cyclooxygenase type 2, increased expression of
adhesion molecules, or synthesis of nitric oxide are indistinguishable
responses of both IL-1 and TLR ligands. Both families nonspecically
affect antigen recognition and lymphocyte function. IL-1 is the most
studied member of the IL-1 family because of its role in mediating autoinammatory diseases. Although the TLR and IL-1 families evolved
to assist in host defense against infection, unlike the TLR family, the
IL-1 family also includes members that suppress inammation, both
specically within the IL-1 family but also nonspecically for TLR ligands and the innate immune response.
519
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INTRODUCTION

IL-1 decoy receptor

(IL-1RII): IL-1 type
II receptor that lacks a
cytoplasmic domain
and thus binds IL-1
but does not transmit a
signal
Single Ig
IL-1-related
receptor (SIGIRR):
functions as an
anti-inammatory
receptor suppressing
inammation
IL-18-binding
protein (IL-18BP): a
naturally occurring,
constitutively secreted
protein that
neutralizes IL-18; it is
not a soluble receptor,
has one Ig-like
domain, and has
limited homology to
the third domain of
the IL-18R
Anakinra: the generic
name for the
recombinant form of
the IL-1Ra (brand
name Kineret);
natural IL-1Ra is
glycosylated, whereas
the recombinant
anakinra is not
Table 1
There are 11 members of the IL-1 family

(IL-1F) of ligands; IL-1, IL-1, IL-1 receptor antagonist (IL-1Ra), and IL-18 have been
thoroughly studied in vitro, in animal models
of disease, and in humans. In humans, blocking
IL-1 activity, particularly IL-1, has entered
clinical medicine. Although within the IL-1
family of ligands separate gene products induce local and systemic inammation, the family also diverged into genes that protect against
runaway inammation and immune responses
(Table 1). For example, IL-1Ra is a specic inhibitor of the activity of both IL-1 and IL-1,
whereas IL-1F5 and IL-1F7 appear to function
as nonspecic inhibitors of inammation and
the innate immune response (1, 2). The most
recent addition to the IL-1 family is IL-1F11
(IL-33). IL-33 is the ligand for the former orphan receptor ST2 (3). IL-33 plays a role in
mast cell functions and drives allergic and Th2
responses. Similar to IL-1, IL-33 can act via
its specic cell surface receptor (ST2); however,
similar to IL-1, IL-33 is an intracellular cytokine and can function as a DNA-binding nuclear factor (4, 5). IL-1F7 also is found in the
nucleus and may act as a nuclear factor (1).
Unlike other cytokine families, the IL-1
family exerts control over inammation at both
the receptor and nuclear levels. Members of the
IL-1 family of receptors contain activators and
suppressors of inammation. For example, the
IL-1 type II receptor (IL-1RII) functions as a
IL-1 family members
New Name
Other Name
Property
IL-1F1
IL-1
Agonist
IL-1F2
IL-1
Agonist
IL-1F3
IL-1Ra
Receptor antagonist
IL-1F4
IL-18; IFN--inducing factor
Agonist
IL-1F5
FIL1
Anti-inammatory
IL-1F6
FIL-1
Agonist
IL-1F7
IL-1H4, IL-1
Anti-inammatory
IL-1F8
IL-1H2
Agonist
IL-1F9
IL-1
Agonist
IL-1F10
IL-1Hy2
Receptor antagonist (?)
IL-1F11
IL-33
Agonist
520
Dinarello
decoy receptor (6), the single Ig IL-1-related

receptor (SIGIRR) suppresses inammation (7,
8), and the IL-18-binding protein (IL-18BP) is
the high-afnity endogenous neutralizer of IL18 activity (9).
IL-1Ra binds tightly to IL-1RI and blocks
the activity of either IL-1 or IL-1. IL-1Ra
(generically known as anakinra) is approved
in several countries for treating the signs,
symptoms, and joint destruction of rheumatoid arthritis. Over 100,000 patients with
rheumatoid arthritis and related diseases have
been treated with IL-1Ra, some for more than
10 years. Blocking IL-1 activity with IL-1Ra
results in an arrest in the progressive joint
space narrowing that is one of the hallmarks of
rheumatoid arthritis. In a placebo-controlled
randomized trial, IL-1Ra appears to benet
patients with stroke (10). IL-1Ra is now
the standard of therapy for patients with
systemic-onset juvenile idiopathic arthritis
(11), refractory adult Stills disease (12), and
several systemic and local inammatory diseases. These chronic inammatory diseases are
now classied as autoinammatory diseases.
The IL-1 Trap, a bivalent construction of the
extracellular domains of IL-1RI and the IL-1R
accessory protein (IL-1RAcP) (13), has been
approved for the treatment of autoinammatory diseases such as familial cold-induced
autoinammatory syndrome (FCAS) and
Muckle-Wells syndrome (14).
For many years, there has been a great
interest in the ability of IL-1 to damage the insulin-producing pancreatic beta cell
(15, 16). But recent studies in humans have
demonstrated a role for IL-1 in diabetes.
In a placebo-controlled, blinded, randomized
trial in patients with poorly controlled type
2 diabetes, 13 weeks of IL-1Ra therapy improved glycemic control and the function of
the insulin-producing beta cell (17). In a second study, neutralizing monoclonal antibodies
to IL-1 also improved glycemic control and
beta cell function in type 2 diabetic patients
(18). Therefore, destruction of the insulinproducing beta cell appears to be an IL-1mediated autoinammatory disease (19).
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Another member of the IL-1 family is IL18BP (9), the naturally occurring inhibitor of
IL-18 activity. IL-18BP has been administered
to patients with rheumatoid arthritis and plaque
psoriasis. IL-18BP is currently being tested in
patients with macrophage activation syndrome
(20).

THE DIFFERENCE BETWEEN

AUTOIMMUNE AND
AUTOINFLAMMATORY DISEASES
The Discovery of Cryopyrin (NALP3)
and the Caspase-1 Inflammasome
Autoinammatory disease is a new classication for chronic inammation with a distinct
therapeutic role for blocking IL-1. In the
1970s, an astute clinical observation in a rare
disease provided us with a greater understanding of chronic inammation. Alan Wanderer
studied patients at the National Jewish Hospital in Denver, Colorado, with cold urticaria
but observed that some patients actually suffered from an autosomal dominant disease associated with cold weather. He called the syndrome familial cold urticaria. Wanderer and
Charles Kirkpatrick studied these patients by
exposing them to 30 min of controlled cold temperatures; soon thereafter, tender, erythematoid macular-like skin eruptions were observed.
Histologically, the exanthem was characterized
by a neutrophilic inltrate. These patients then
developed severe constitutional symptoms with
chills, fever, fatigue, and joint aches. Leukocytosis (primarily neutrophilia) followed within
a few hours. As systemic symptoms developed
over days, colleague Patsy Giclas observed elevations in acute-phase reactants. A debilitating disease, cold urticaria led patients to live in
warm climates to avoid the cold. They appeared
to have an acute infection, with elevated acutephase proteins and leukocytosis, but in fact their
symptoms were triggered simply by exposure to
cold.
Wanderer asked Hal Hoffman, the young
immunogeneticist son of Wanderers colleague
Leonard Hoffman, to identify the gene in this
disorder to understand better the underlying

pathogenic mechanisms. Owing to the systemic
nature of the disease, Hoffman changed the
name of the syndrome from familial cold urticaria to familial cold autoinammatory syndrome (FCAS). Genetic analysis revealed that
these patients possessed single nucleotide mutations in the coding region of a particular gene,
which he named cold-induced autoinammatory syndrome-1 (CIAS1). This gene coded for
an intracellular protein, which Hoffman termed
cryopyrin because the patients developed fever
following exposure to cold (21). Subsequently,
the name for CIAS1 was changed to nucleotidebinding oligomerization domain (NOD)-like
receptor protein 3 (NLRP3) because it was a
member of the large NOD-like receptor (NLR)
family of genes important in the regulation of
innate immune functions (22). Because it has
become clear that cryopyrin functions in several
inammatory diseases unrelated to FCAS, it is
commonly called NALP3, which accurately describes its common structural domains. NALP3
associates by oligomerization with other intracellular proteins by protein-protein interactions to form a complex known as the inammasome (2325). The inammasome functions to
convert inactive procaspase-1 to active caspase1, which cleaves the inactive IL-1 precursor
to a secreted, active cytokine. Caspase-1 also
cleaves the precursors of IL-18, IL-33, and IL1F7. Unlike members of the IL-1 family, the
inammasome plays no role in the activity of
tumor necrosis factor (TNF)-. Since the pivotal discovery of NALP3 (cryopyrin), there has
been greater understanding of systemic and local inammation.
Characteristics of Autoinflammatory
Diseases
Autoinflammatory
diseases: a diverse
group of inammatory
diseases primarily
mediated by IL-1,
some of which are due
to mutations in the
proteins that comprise
the inammasome and
result in increased
secretion of active
IL-1, but most of
which have no known
mutations in the
inammasome
IL-1 receptor
accessory protein
(IL-1RAcP): forms a
dimer with either the
IL-1RI or the
IL-33R chain (ST2)
and is required for
signal transduction for
IL-1 and IL-33; it also
forms a complex with
the IL-1RII and
IL-1, blocking IL-1
activity
Type 2 diabetes:
adult-onset diabetes in
which the beta cells
are still present in the
pancreatic islet (unlike
in type 1) but the
peripheral tissues are
unable to use insulin
(known as insulin
resistance)
NOD: nucleotidebinding
oligomerization
domain
NLR: NOD-like
receptor
Although nearly all autoimmune diseases have

an inammatory component, some diseases appear to be primarily inammatory in nature because of their periodicity, strong associations
with exogenous triggering events, and lack of
associations with class II MHC haplotypes.
In comparison, autoimmune diseases exhibit
www.annualreviews.org Functions of the IL-1 Family
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Inflammasome:
a complex of
intracellular
interacting proteins
(oligomerization) that
initiates the
autocatalysis of
procaspase-1 into an
active enzyme
P2X7 receptor: a
purinergic receptor
that participates in the
activation of the
inammasome and
caspase-1
Table 2
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distinct MHC-associated haplotype susceptibilities, are progressive rather than periodic,

and are not strongly associated with environmental stress triggers. Moreover, autoinammatory diseases include diseases that are due to
specic mutations in proteins that regulate IL1 activity and not TNF- activity. As such,
autoinammatory diseases are highly responsive to IL-1 blockade and not TNF- neutralization, whereas autoimmune diseases are
responsive to anti-TNF- agents. Other therapies such as CTLA4-Ig and anti-IL-12/IL-23
are also effective in treating patients with autoimmune diseases but have no effect in patients
with autoinammatory diseases. Table 2 lists
autoinammatory diseases that consistently respond rapidly to blocking IL-1. Table 3
lists the therapeutic options for reducing IL-1
activity.
Autoinflammatory diseases1
Familial Mediterranean fever

Familial cold autoinammatory syndrome (FCAS)
Muckle-Wells syndrome
Neonatal-onset multi-inammatory disease (NOMID)
Mevalonic aciduria
Hyper IgD syndrome
Adult-onset Stills disease
Systemic-onset juvenile idiopathic arthritis
Schnitzlers syndrome
Anti-synthetase syndrome
TNF receptorassociated periodic syndrome
Macrophage activation syndrome2
Behcets syndrome
Normocomplementemic urticarial vasculitis
Pericarditis
PAPA syndrome
Blaus syndrome
Sweets syndrome
Urate crystal arthritis (gout)
Type 2 diabetes3
1
Responsive primarily to IL-1 blockade.

IL-18 likely contributes to the macrophage activation syndrome (20).
3
IL-1 blockade with IL-1Ra (17) or anti-IL-1 monoclonal antibody (18) protects the
insulin-producing beta cells. Hyperglycemia stimulates IL-1 secretion from the beta cell
and accounts for the loss of the beta cell mass in type 2 diabetes (109).
2
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Dinarello
The pathological mechanism of increased

secretion of active IL-1 in autoinammatory
diseases is usually but not always dysfunctional
activation of caspase-1. In general, the release
of active IL-1 from blood monocytes is tightly
controlled; less than 20% of the total synthetic
IL-1 precursor is processed and released. In
contrast, monocytes from patients with autoinammatory syndromes release more processed
IL-1, but the increase is modest, that is, less
than tenfold greater than that of monocytes
from healthy subjects. In circulating human
blood monocytes, caspase-1 can be present in
an active state (26); as soon as the monocyte
is stimulated, cleavage of the precursor takes
place, and active IL-1 is secreted.
Although it is possible to demonstrate that
monocytes from patients with autoinammatory diseases process and release signicantly
more IL-1 than do monocytes from healthy
controls (11, 2729), the basis for the increase
varies. Several autoinammatory diseases have
a mutation in NALP3, resulting in a single
amino acid change in the protein and an active inammasome (21, 22, 2831); however,
the same autoinammatory diseases with the
same clinical characteristics do not have mutations in genes known to regulate caspase-1
or the secretion of IL-1. For example, the secretion of IL-1 appears to require triggering
of the P2X7 purinergic receptor by ATP (32)
and active phospholipases C and A2b for secretion via secretory lysosomes (33). Regardless of
the mechanism of increased IL-1 release, what
characterizes these diseases as autoinammatory is the rapid and sustained response to a
reduction in IL-1 activity.
Autoinammatory diseases are syndromes. They include neonatal-onset multiinammatory disease (NOMID), MuckleWells syndrome, FCAS, hyper IgD syndrome,
familial Mediterranean fever, and urate crystal
arthritis (gout) (see Table 2). Some of these
syndromes are rare, but the clinical manifestations are common to nearly all inammatory
as well as infectious diseases. As discussed
below, type 2 diabetes mellitus and gout are
autoinammatory diseases and are hardly
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Table 3
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Specific therapies for blocking IL-1 activities
Reagent
Composition
Mechanism of action
Specificity
Anakinraa
IL-1Ra
binds to IL-1RI>IL-1>IL-1
IL-1 and IL-1
IL-1Ra trimer
IL-1Ra
binds to IL-1RI>IL-1>IL-1
IL-1 and IL-1
IL-1 Trapb
IL-1RI + IL-1RAcP
neutralizes IL-1>IL-1>IL-1Ra
IL-1 (IL-1)
Soluble
IL-1RIIc
IL-1RII
neutralizes IL-1>IL-1
IL-1
Anti-IL-1
monoclonal antibody
neutralizes IL-1
IL-1
Anti-IL-1RI
monoclonal antibody
blocks IL-1RI
IL-1 and IL-1
Anti-IL-1RAcP
monoclonal antibody
blocks IL-1RAcP
IL-1 and IL-1, IL-33
Peptide antagonistd
RYTVELA
blocks IL-1RI
IL-1 and IL-1

Anakinra is the recombinant (nonglycosylated) form of IL-1Ra. Naturally occurring IL-1Ra is the glycosylated gene product.
Bivalent with Fc.
c
Efcacy of the extracellular IL-1RII is greatly enhanced by the presence of extracellular IL-1RAcP (164, 166).
d
Inhibits some but not all IL-1 activities (158).
b
rare conditions. One important criterion for

characterizing a disease as autoinammatory
is that upon blocking IL-1 rather than TNF activity, patients experience a rapid and
sustained cessation of symptoms as well as
reductions in biochemical, hematological, and
functional markers of their disease. Given that
treatment with the IL-1 Trap or monoclonal
anti-IL-1 antibodies are equally effective
in treating autoinammatory diseases, the
culprit in these diseases is IL-1 and not
IL-1. Another criterion for classication of
an autoinammatory disease is a reduction
in disease severity with the use of specic
inhibitors of caspase-1, which targets the
processing and secretion of IL-1.
OVERVIEW OF THE IL-1 FAMILY

IN INFLAMMATORY RESPONSES
Unlike IL-2 and other cytokines that directly
affect lymphocyte function, differentiation, and
expansion, most members of the IL-1 family primarily do not directly affect lymphocyte
function. As such, the effect of IL-1 family
members on immune functions is indirect. For
example, the ability of IL-1 to induce gene expression and synthesis of cyclooxygenase type
2 (COX-2), type 2 phospholipase A, and inducible nitric oxide synthase (iNOS) accounts
for prostaglandin-E2 (PGE2), platelet activating factor, and nitric oxide (NO) production.
As a result, there is fever, lowered pain threshold, vasodilatation, and hypotension. However,
these products also affect immune responses.
For example, PGE2 is perhaps the most common mechanism for nonspecic suppression of
T cell responses.
Another important proinammatory property of IL-1 is its ability to increase the expression of adhesion molecules such as intercellular adhesion molecule-1 on mesenchymal
cells and vascular cell adhesion molecule1 on
endothelial cells. Together with the induction
of chemokines, these properties of IL-1 promote the inltration of inammatory and immunocompetent cells from the circulation into
the extravascular space and then into tissues
where tissue remodeling is the end result of
chronic IL-1-induced inammation. IL-1 is
also an angiogenic factor (34) and plays a role
in tumor metastasis and blood vessel formation. In mice decient in IL-1, vascular endothelial cell growth factor (VEGF) cannot
stimulate formation of blood vessels, and malignant melanoma cells do not spread. IL-1
also acts on bone marrow stem cells for differentiation of the myeloid series of progenitor cells. In humans injected intravenously with
low doses of IL-1 of 110 ng/kg, there is
fever and increased levels of ACTH, blood neutrophils, NO, acute-phase proteins, and several
cytokines and chemokines. IL-6 production is
particularly sensitive to IL-1, and a dose of
523
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1 ng/kg results in high levels of IL-6 (reviewed

in 35). Blocking IL-1 in systemic diseases reduces IL-6 levels (36).
OVERVIEW OF THE IL-1 FAMILY

IN IMMUNE RESPONSES
IL-1 Family Members as
Costimulators of T Cells

IL-1 (IL-1 or IL-1) functions as a costimulator of T cell functions, primarily together

with an antigen or a mitogen. IL-18 alone does
not stimulate IFN- but rather acts as an essential coactivator with IL-2, IL-12, or IL-15,
although the combination of IL-18 plus IL-12
is perhaps uniquely effective at inducing IFN. IL-33 is also an activator of T cells, but in this
case the function of IL-33 is to promote a Th2
response (3, 37). IL-1 can act as a growth factor
for thymocytes. Human thymic epithelium produces constitutive levels IL-1 and contributes
to the proliferation of thymocytes. However,
it is unlikely that IL-1 plays an essential role
in thymic growth and function given that mice
decient in IL-1, IL-1, or the IL-1RI have
normal thymic development. As with IL-1,
IL-18 is strongly expressed in thymic epithelial
cells.
IL-1 and Th2 Immune Responses

In some models, IL-1 contributes to Th2 polarization. For example, in murine models of
asthma using airway sensitization to antigens,
the responses to antigen challenge are increased airway responsiveness to bronchoconstricting agents, inltration of the lungs by
eosinophils, and increased expression of IL4. However, in mice decient in IL-1RI or
treated with neutralizing anti-IL-1 antibodies, the response to inhaled antigen is markedly
reduced (38). Using airway sensitization with
ovalbumin, eosinophil, and neutrophil inltration following inhalation, antigen challenge
was prevented in mice expressing IL-1Ra adenovirus (39). Suppression of IL-5 was also
observed.
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Dinarello
IL-1 and B Cell Functions

A role for IL-1 in antibody production has
been repeatedly reported. For example, mice
decient in IL-1 do not produce antisheep
red blood cell antibodies, a T-dependent response (40). However, antibody production by
T-independent antigens was normal in mice decient in both IL-1 and IL-1, as was the proliferative response to anti-CD3. The evidence
that IL-1 is a growth factor for B cell proliferation may be due to IL-1-mediated induction
of IL-6. In fact, in vitro and in vivo, IL-6 is often under the control of IL-1. A nonopeptide
in the IL-1 sequence is a potent adjuvant, and
this activity is independent of IL-6 (41).
IL-1 and Th17

During the generation of the Th17 response,
IL-1 appears essential given that T cells from
mice decient in IL-1RI fail to induce IL-17
upon antigen challenge (42). Moreover, IL-23
fails to sustain IL-17 in IL-1RI-decient T
cells. IL-23 is believed to mediate celiac disease, an autoimmune disease in which 95% of
patients are positive for HLA-DQ2. Production of IL-23 in monocytes from these patients
by beta-glucan is IL-1 dependent (43). The
combination of IL-23 plus either IL-1 or IL1 is synergistic in the induction of IL-17. Even
TNF- enhancement of IL-23-induced IL-17
is IL-1 dependent. In some studies in mice,
TGF- and IL-6 are required for differentiation of Th17 T cells. In a recent study, IL-6
was reported to induce Th17 cells when costimulated with TGF- (44). In that study, IL-1
and TNF- were not effective. Although supernatants from LPS-stimulated bone marrow
dendritic cells induced IL-17 production from
naive T cells, an IL-6 receptorblocking antibody had no effect (44). TGF- secretion from
LPS-stimulated dendritic cells is low or absent.
The addition of exogenous mixtures of recombinant cytokines often results in production of IL-17. For example, the combination of
IL-6 and TGF- induces IL-17, and this combination maintained the activation of STAT3

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(44). Here the role of STAT3 activation is relevant for the induction of the transcription factor
retinoic acidrelated orphan receptor gamma.
Another STAT3-activating cytokine is IL-23,
which sustains IL-17-producing cells. Therefore, there is likely a cascade of IL-1-induced
IL-6 and IL-23 for Th17 induction, as both
IL-6 and IL-23 are IL-1 dependent. However, there is also the exception that the addition of exogenous IL-1 can result in the
suppression of IL-6 phosphorylation of STAT3
(45). Specic cytokine blockade or a cytokine
deciency state reveals the functional consequence of a cytokine in immune responses.
Because a highly specic antibody that prevents the activity of IL-6 had no effect on the
ability of LPS-stimulated dendritic cell supernatants to induce IL-17, the data suggest that
IL-6 is not the naturally occurring cytokine
from antigen-presenting cells that accounts for
the polarization of CD4+ cells into a Th17
population.
In human cord blood T cells, IL-1 induced
polarization of Th17 cells, and this effect was
enhanced by IL-6 but suppressed by TGF-
(45). Others also report the antagonism of IL1-induced IL-17 in human cells by TGF-
(46). That TGF- suppressed the response is
hardly unexpected, as antagonism between IL1 (or IL-18) and TGF- is often reported
(47, 48), particularly in T cells (reviewed in 35).
In the mouse, however, TGF- enhances the
differentiation to Th17. Monocytes can prime
CD4+ T cells for IL-17 production via IL-1
and IL-6 secretion, but not via IL-12 (45). Although there are several reports that IL-1 can
synergize with IL-6 in models of T cell activation and angiogenesis, IL-1 can also antagonize the action of IL-6 by suppressing IL-6
phosphorylation of STAT3 as well as by inducing SOCS3 (49).
The requirement of IL-1 in the generation
of Th17 cells is consistent with mice decient
in IL-1Ra. Lacking this naturally occurring antagonist of IL-1 activity, IL-1Ra-decient mice
exhibit unopposed IL-1 activity and spontaneously develop a rheumatoid arthritislike disease, but mice decient in IL-17 do not (50).
Furthermore, IL-1 activation of the cosignaling receptor OX40 induces IL-17. Taken together, the data indicate that IL-1 is upstream
of both OX40 activation and IL-17 production. These ndings are consistent with the
observation that mice decient in both IL-1
and IL-1 do not develop experimental autoimmune encephalomyelitis (EAE) (51). Several studies show that IL-1 and IL-17 act synergistically on the induction of NO, PGE, and
cartilage breakdown. Not unexpectedly given
that IL-1 induces IL-17, IL-17 in turn stimulates the production and release of IL-1
from primary human blood monocytes. In general, proinammatory cytokines induce each
other.
IL-18 Is Both a Th1 and Th2 Cytokine

Because IL-18 participates with IL-12 and IL15 in the production of IFN-, IL-18 contributes to the Th1 response; however, there is
a well-described role for IL-18 in the Th2 response (52). For example, IL-18 induces IL-4,
resulting in increased numbers of IL-4-positive
cells from activated natural killer (NK) T cells
in the absence of IL-12. In general, the presence of IL-12 shifts the activity of IL-18 toward IFN- and the Th1 response, whereas
IL-18 in the absence of IL-12 drives the Th2 response. Combined overexpression of IL-18 and
caspase-1 results in the development of spontaneous atopic dermatitis with increased expression of Th2 cytokines and IgE (53). In transgenic mice overexpressing IL-18, serum levels
of IgE, IgG1, IL-4, and IFN- were significantly increased (54). Therefore, high IL-18
production can polarize toward both Th1 and
Th2 responses. Although IL-18 shares may of
the same proinammatory properties with IL1, IL-18 can also counter the effects of IL-1
(55).
DEFICIENCY IN IL-1 FAMILY

MEMBERS
Mice decient in IL-1RI, IL-1RAcP, IL-1, or
IL-1 or doubly decient in IL-1 and IL-1
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exhibit no phenotypical differences from samestrain wild-type mice, and they live in routine
animal facilities. One can conclude that IL-1
or IL-1, which play important roles in disease, are not essential for normal embryonic development, postnatal growth, homeostasis, reproduction, or resistance to routine microbial
ora. Also, these mice do not exhibit evidence
of spontaneous carcinogenesis, their life span
appears normal, and lymphoid architecture is
also normal. In contrast, in models of local or
systemic inammation, a deciency in IL-1 activity usually results in reduced disease severity
but increased susceptibility to live infections.
However, mice decient in IL-1Ra exhibit reduced reproduction, have stunted growth, and
develop spontaneous diseases such as rheumatoid arthritislike polyarthropathy (56), a fatal
arteritis (57), and tumors in response to chemical carcinogens (58). Thus, one can conclude
that without natural IL-1Ra, IL-1-induced inammation is unchecked.
PRO- AND ANTI-INFLAMMATORY

FUNCTIONS WITHIN
THE IL-1 FAMILY
The IL-1 family also includes members that suppress inammation, both specically within the IL-1 family but also nonspecifically for TLR ligands and other cytokines. The suppression can
be highly specic. For example, the IL-1 receptor antagonist, a
bona de member of the family, binds to the IL-1 receptor type
I with a greater afnity than IL-1 itself and reduces IL-1 and
IL-1 responses. The soluble form of the IL-1RAcP is constitutively produced by the liver and forms a complex with the soluble
IL-1RII, which binds and neutralizes IL-1. The IL-18-binding
protein binds and neutralizes IL-18 owing to an afnity for IL18 that is greater than the IL-18 receptor. IL-1 family member
seven is a nonspecic anti-inammatory cytokine. IL-1F7 suppresses IL-1, TNF-, and TLR ligand activities. SIGIRR is also
a nonspecic inhibitor of inammation. IL-33, the ligand for the
orphan receptor ST2, can shift a Th1 response induced by IL-18
into a Th2 response. Thus, the IL-1 family of ligands and receptors evolved with the dual role of defending the host via the
innate immune response as well as specically and nonspecically
reducing inammation.
526
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Similarly, mice decient in IL-18 exhibit reduced responses in several models of disease.
For example, IL-18-decient mice are resistant
to endotoxin lethality, collagen-induced arthritis, Fas ligandmediated hepatitis, graft-versushost disease, ConA-induced hepatitis, and allograft rejection. However, as discussed below,
mice decient in IL-18 or IL-18R become
obese with increasing age and develop nearly
all the parameters of the metabolic syndrome
observed in humans (59).
THE DIVERSITY OF
THE IL-1 FAMILY
Table 1 lists the current members of the IL1 family and their primary function. In this
review, I retain the terms IL-1, IL-1, IL18, and IL-33 as well as IL-1Ra. With the exception of IL-18 and IL-33, the members of
the IL-1 family are located on the long arm
of chromosome 2. From the intron-exon organization, some members represent gene duplications. In the case of IL-1F5 and IL-1F10,
the duplication of the IL-1Ra gene has taken
place (60). IL-1F9 is also related to IL-1Ra but
does not function as a receptor antagonist but
rather as an agonist. IL-33 (IL-1F11) is closely
related to IL-18. However, as described below, the activity of an individual IL-1 family
member is not determined by its structure but
rather by its ability to transmit an agonist signal or act as a receptor antagonist. Two members of the IL-1 family (IL-1F5 and IL-1F7)
appear to function as broad anti-inammatory
cytokines. Equally important to the diversity of
the IL-1 family is the role of the IL-1 family of
receptors. Whereas those receptors transmitting an inammatory signal are well studied,
those transmitting an anti-inammatory signal
are of considerable importance in regulating
inammation.
IL-1 (IL-1F1)
IL-1 as an autocrine growth factor. Calpain, a calcium-activated cysteine protease associated with the plasma membrane, can cleave

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the IL-1 precursor into a mature molecule.

However, even under conditions of cell stimulation, human blood monocytes do not process or readily secrete mature IL-1. IL-1 is
not commonly found in the circulation or in
body uids, except that the cytokine may be released from dying cells (61). One distinguishing property of IL-1 is that its precursor form
is active. Most cell lines, including tumor cell
lines, contain constitutive levels of IL-1 (4,
62, 63). The concept that IL-1 acts as an autocrine growth factor assumes that the intracellular IL-1 precursor regulates normal cellular differentiation, particularly in epithelial
and ectodermal cells. In support of the concept,
an antisense oligonucleotide to IL-1 reduces
senescence in endothelial cells (64). In broblasts, the constitutive IL-1 precursor binds
to HAX-1, a nonreceptor substrate for tyrosine
kinases in hematopoietic cells. In broblasts,
the IL-1 HAX-1 complex translocates to the
nucleus (65). The complex seems to function
because suppression of HAX-1 results in a failure of IL-1 to bind to DNA, resulting in reduced production of IL-6 and procollagen (65).
Although some accept the concept that IL-1
acts as an autocrine growth factor in broblasts
or endothelial cells in vitro, the data must be interpreted carefully given that mice decient in
IL-1 show no demonstrable defects in growth
and development, including skin, fur, epithelium, or gastrointestinal function (66). However, mice decient in IL-1 still retain the
propiece, which functions as a nuclear factor.
In fact, in another study, the N-terminal propiece of IL-1 bound HAX-1 (67). At present,
there is no absolute IL-1-decient mouse
model.
Is there a role for intracellular precursor IL1 in normal cell function? The IL-1 precursor is expressed constitutively in all epithelial cells, and large amounts of the intracellular
form of the IL-1Ra (icIL-1Ra) are also present
in these same cells (68). This form of the IL1Ra also binds to the IL-1RI and prevents signal
transduction. In fact, icIL-1Ra is produced in
the same cells expressing the IL-1 precursor
and is thought to compete with the intracellular pool of precursor IL-1 for nuclear binding
sites.
Membrane IL-1. Precursor IL-1 can be
found on the surface of several cells, particularly
on monocytes and B lymphocytes, where it is referred to as membrane IL-1 (69). Membrane
IL-1 is biologically active (70); its biological
activities are neutralized by antibodies to IL-1
but not against IL-1. Membrane IL-1 plays
an important role in inammation, as mice decient in IL-1 exhibit reduced inammation
in models in which cell death and the release of
intracellular IL-1 do not take place (71).
Biological functions of constitutive IL-1.
Primary cells contain constitutive levels of the
IL-1 precursor and not IL-1 (72). Not surprisingly, because the IL-1 precursor is biologically active and found in normal epithelial cells, including thymic epithelium, contents
from necrotic cells will contain biologically active IL-1 (61). It is well known that contents
of necrotic cells are inammatory, and hence
their activity is due to IL-1 present in either
the cytosol or the membrane fraction (4). Even
if a cell contains the IL-1 precursor, any biological activities of its contents would be due to
IL-1 because the IL-1 precursor is inactive
(72). Furthermore, epithelial cells do not contain caspase-1, and therefore processing of the
IL-1 or IL-18 precursor cannot yield the biologically active forms of either cytokine. Constitutively expressed IL-1 is critical for several
IFN- activities. Using the WISH epithelial
cell line, what were considered to be intrinsic
IFN- activities depended largely on constitutively expressed IL-1. IFN- activities were
inhibited in antibodies to IL-1, but not to IL1 (63). Others report that antibodies to IL-1
and not IL-1 prevent the biological activities
of necrotic cells (61).
Studies in IL-1-deficient mice. Mice decient in IL-1 are born healthy and develop
normally. Following subcutaneous injection of
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turpentine, which induces a local inammatory response, wild-type and IL-1-decient

mice develop fever and acute-phase proteins,
whereas IL-1-decient mice do not (66). In
addition, although the induction of glucocorticoids after turpentine injection was suppressed
in IL-1-decient mice, this suppression was
not observed in IL-1-decient mice. However, expression of IL-1 mRNA in the brain
decreased 1.5-fold in IL-1-decient mice,
whereas expression of IL-1 mRNA decreased
more than 30-fold in IL-1-decient mice.
These data suggest that IL-1 exerts greater
control over production of IL-1 than does IL1 over the production of IL-1. In caspase1-decient mice, IL-1 production is also reduced (73), suggesting that production of IL-1
is under the control of IL-1.
The effects of IL-1 on atherogenesis by a
high-cholesterol diet was evaluated in mice decient in either IL-1 or IL-1 (71). Serum
amyloid A protein, a marker of inammation
in atherogenesis, was markedly lower in IL1-decient mice compared with wild-type or
IL-1-decient mice. The benecial effect of
IL-1 deciency was due to bone marrow cells.
Transplantation of bone marrow cells from IL1-decient mice resulted in a reduction in
aortic lesion size twice that observed in mice
transplanted with IL-1-decient bone marrow cells. Therefore, IL-1 appears to play
a greater role in the pathogenesis of lipidmediated atherogenesis than does IL-1, and
this may be due to an effect of membrane
IL-1.

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IL-1 (IL-1F2)
Dissociation between transcription and
translation. 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 signicant translation into the IL-1 protein. The IL-1 mRNA
assembles into large polyribosomes, but without signicant elongation of the peptide (74),
and most of the IL-1 mRNA is degraded. In
528
Dinarello
IL-1, IL-18, and IL-1F7, an instability element in the coding region accounts for the failure to translate the mRNA into protein (75).
However, adding TLR ligands or IL-1 itself to
monocytes with high levels of IL-1 mRNA
results in augmented translation (76).
Regulation of IL-1 production. 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
sites. IL-1 gene regulation has been reviewed
in detail (77). The primary sources of IL-1
are the blood monocyte, tissue macrophages,
and dendritic cells. B lymphocytes and NK
cells also produce IL-1. Fibroblasts and epithelial cells generally do not produce the cytokine, however. Circulating blood monocytes
or bone marrow aspirates from healthy humans
do not constitutively express mRNA for IL-1.
In contrast, several malignant tumors express
IL-1 as part of their neoplastic nature, particularly acute myelogenous leukemia, melanoma,
multiple myeloma, and juvenile myelogenous
leukemia, each of which exhibits constitutive
expression of IL-1.
Although nearly all microbial products induce IL-1 via TLR ligands, IL-1 induces itself both in vivo and in monocytes in vitro
(78). Other studies supporting this concept have
been reported (27, 79, 80). Following LPS stimulation, IL-1 mRNA levels rise rapidly within
15 min but begin to decline after 4 h owing
to mRNA half-life or the action of microRNA.
However, using IL-1 itself as a stimulant, IL-1
mRNA levels are sustained for over 24 h compared with microbial stimulants (81). Raising
intracellular cAMP levels with histamine enhances IL-1-induced IL-1 gene expression and
protein synthesis. As shown in Figure 1, the
IL-1 precursor accumulates in the cytosol, and
processing by caspase-1 is triggered by ATP activating the P2X7 receptor. In freshly cultured
human blood monocytes, endogenous levels of
ATP rise and are sufcient for triggering the
assembly of the inammasome (26).
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Active
IL-1
1 IL-1
IL-1RI
IL-1RAcP
Secretion
of IL-1 9
ATP
trigger
Active
IL-1
5a
K+
eux
Ca2+
entry
Ca2+
8
P2X7 R K channel
Caspase-1

MyD88
Processing
7 of IL-1
Secretory lysosome
9 Secretion
of IL-1
K+ 5b
7 Processing
of IL-1
Caspase-1
3 Translation
of IL-1
precursor
2 Transcription
Assembly of 6
inammasome
ASC
Procaspase-1 CARD CARD

Procaspase-1 CARD
CARD FIIND
PYR
PYR NACHT NAD
LRR
NALP3 (cryopyrin)
IL-1 mRNA
Cardinal
NALP3 inammasome
Figure 1
Steps in the synthesis and secretion of IL-1 induced by IL-1. Primary blood monocytes or tissue macrophages are activated by
IL-1 (78) (step 1). The formation of the IL-1 receptor complex heterodimer results in approximation of the Toll IL-1 receptor (TIR)
domains (red ) and the recruitment of MyD88. The transcription (step 2) and translation into the IL-1 precursor (step 3) are separate
events. Translation takes place in the cytosol, not in the endoplasmic reticulum. The activated monocyte/macrophage releases ATP into
the extracellular space (26). Upon activation of the P2X7 receptor by ATP (step 4), there is a rapid efux of potassium from the cell
(step 5a) resulting in a fall in intracellular levels of potassium (step 5b). The fall in intracellular potassium levels triggers the assembly of
the components of the NALP3 inammasome (step 6). Given that NALP3 (cryopyrin) does not contain a caspase-activating recruiting
domain (CARD), the adaptor protein termed apoptosis-associated speck-like protein containing a C-terminal CARD (ASC) is required
together with CARDINAL for oligomerization. The assembled components of the inammasome initiate the processing of
procaspase-1, resulting in the formation of the active caspase-1. Active caspase-1 processes the IL-1 precursor (step 7) in the cytosol
or in the secretory lysosome, resulting in the generation of the carboxy-terminal mature IL-1. An inux of calcium into the cell (step
8) with an increase in intracellular calcium levels (33, 169) provides a mechanism by which mature IL-1 is released from the cell (step
9). The rise in intracellular calcium activates phosphatidylcholine-specic phospholipase C and calcium-dependent phospholipase A(2),
which facilitate the secretion of IL-1 (step 9) with exocytosis of the lysosomal contents (33). Other pathways exist for processed IL-1
to exit the cell (see text).
Processing and secretion of IL-1 via the

caspase-1 inflammasome. Regardless of the
stimulus, in monocytes and macrophages specic inhibitors of caspase-1 reduce the secretion of mature IL-1, and precursor IL-1
accumulates mostly inside the cell. The ratelimiting step in the processing and secretion of
IL-1 takes place with activation of the inam-
masome. As shown in Figure 1, several intracellular proteins form a complex with NALP3.
As discussed above, NALP3 was initially discovered in patients with FCAS, a genetic
disease characterized by constitutional symptoms, fevers, and elevated acute-phase proteins
following exposure to cold (21). Assembly of
the inammasome components with inactive
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CARD: caspaseactivating recruiting

domain

ASC: apoptosisassociated speck-like

protein containing a
C-terminal CARD
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procaspase-1 takes place following a fall in intracellular potassium (Figure 1). ATP activation of the P2X7 receptor opens the potassium
channel, and simultaneously as potassium levels fall caspase-1 is activated by the inammasome (33, 8284). NALP3 is unique among the
NLRPs in that there is no caspase-activating recruiting domain (CARD). Therefore, the adaptor protein termed apoptosis-associated specklike protein containing a C-terminal CARD
(ASC) provides the linkage of the pyrin domain
(PYR) on NALP3 to the CARD domain on
procaspase-1 (see Figure 1). Another protein
(CARDINAL) is also part of the oligomerization of the inammasome.
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 pathways include exocytosis of the secretory lysosomes (33, 82), shedding of plasma membrane
microvesicles, direct release via transporters,
or multivesicular bodies containing exosomes
(85). In general, the release of processed IL1 takes place before there is signicant release
of lactate dehydrogenase (86), although in vitro
cell death eventually takes place. Pyroptosis is
a caspase-1-dependent form of cell death and is
employed by certain bacteria using Ipaf, a member of the NLR family of intracellular receptors
(87). An increase in intracellular calcium is also
required for the mature IL-1 to exit the cell,
and it is phospholipase C dependent (33).
The function of the caspase-1 inammasome is primarily to convert inactive
procaspase-1 into the active enzyme, and this
step requires activation of the P2X7 receptor
by ATP. However, in freshly obtained human
blood mononuclear cells from healthy subjects,
the p10 subunit of active caspase-1 is present
even in the absence of stimulation (26), and,
during the subsequent incubation, extracellular levels of ATP increase (26). Upon differentiation into macrophages, activation of the
inammasome requires exogenous ATP (26).
But in monocytes from patients with a single
amino acid mutation in NALP3, activation of
Dinarello
caspase-1 occurs without a requirement for a

rapid fall in the level of intracellular potassium
(28). Therefore, mutated NALP3 allows for the
assembly of the complex of interacting proteins
in the presence of normal intracellular levels of
potassium. Although this process is often studied using LPS-induced synthesis of the IL-1
precursor (88), LPS likely does not play a role
in autoinammatory diseases. However, spontaneous secretion of IL-1 from monocytes
of patients is due to endogenous IL-1 stimulation. In patients with NOMID, there is a
decrease in steady-state levels of procaspase-1
mRNA with IL-1Ra treatment (27), suggesting
that IL-1 stimulates its own production and
processing (see Figure 1). Thus, any disease
process that includes an increase in the steadystate levels of procaspase-1 mRNA, components of the inammasome, or the IL-1 precursor explains the autoinammatory nature
of the disease. Type 2 diabetes appears to be
an example of an autoinammatory disease in
which glucose induces IL-1 production from
the insulin-producing beta cell, and IL-1 induces the beta cell to produce its own IL-1
(19).
P2X7 and the activation of the inflammasome. Patients with classic autoinammatory
diseases such as familial Mediterranean fever or
NOMID have nearly identical clinical parameters, secrete more IL-1, and respond dramatically to IL-1 receptor blockade, yet they have
no mutation in NALP3. It is therefore possible
that mutations in P2X7 itself or regulation of
the other genes controlling potassium channels
(11) may account for dysfunctional secretion of
IL-1. For example, monocytes from patients
with rheumatoid arthritis are more sensitive to
release of IL-1 following ATP activation of
the P2X7 receptor compared with monocytes
from healthy controls (89). However, monocytes from subjects with a P2X7 Glu496Ala
loss-of-function polymorphism secrete significantly less IL-1 (90). Monocytes from subjects homozygous for this polymorphism also
release signicantly less IL-18 (91). Another
P2X7 receptor polymorphism is associated with

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increased mortality in patients undergoing allogenic stem cell transplantation (92). Bacteremia
was documented in 68% of patients with this
polymorphism compared with 18% in wildtype control patients (92).
Mice decient in P2X7 receptors exhibit
markedly reduced inammation, pain, and IL1-mediated IL-6 production (93). In addition
to a fall in intracellular potassium, ATP triggers formation of peroxynitrite, which is required for caspase-1 activation, based on the
observation that peroxynitrite scavengers prevent IL-1 secretion (94). Pannex-1, 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 (95). Pannexin-1 can also function in
LPS-induced IL-1 synthesis in the absence of
TLR4 (96). P2X7 receptor activity is also regulated by regeneration and tolerance factor (97).
Inactive IL-1 precursor (31 kDa)

Active, mature IL-1 (18 kDa)
N terminus
Y V H D A P V ............ C terminus
116

N terminus
E S D Y F G K L ............ C terminus
37

N terminus
A L H D S S
114
Inactive IL-1F7 precursor (25 kDa)

IL-1F7 (22 kDa)
N terminus 18aa E
Noncaspase-1 processing of IL-1.

Figure 2 illustrates the caspase-1 cleavage sites of the IL-1, IL-18, IL-33, and
IL-1F7 precursors. However, for each of these
cytokines, noncaspase-1 mechanisms also exist
and generate active forms. For example, sterile
inammation induces fever, elevated IL-6, and
increased production of hepatic acute-phase
proteins. These responses are absent in mice
decient in IL-1 but present in mice decient
in caspase-1 (98). Sterile inammation is
often associated with neutrophilic inltration,
and neutrophils produce IL-1. Because
neutrophils are short-lived cells, dying within
hours after emigration, release of the IL-1
precursor from intracellular stores is not unexpected. Therefore, processing of the IL-1
precursor extracellularly into an active cytokine
has been reported for the common neutrophil
protease proteinase-3 (99). Proteinase-3 also
contributes to the processing of IL-18 (100).
Other proteases such as elastase, matrix metalloprotease 9, and granzyme A process the
IL-1 precursor extracellularly. In addition, a
mast cell chymase generates active IL-1.
Mice with a targeted IKK deletion in
myeloid cells are more susceptible to LPS-
I ............ C terminus
K D
P Q C ............ C terminus
Figure 2
Four substrates for caspase-1. Caspase-1 cleaves the IL-1, IL-18, IL-33, and
IL-1F7 precursors at the aspartic acid in P1 position. Shown are the amino acid
lengths of the mature cytokines. The true N terminus for IL-1F7 may not be at
the caspase-1 site. Caspase-1 site cleavage was reported as forming a 22-kDa
peptide, but no amino acid sequence is known (126).
induced shock than are control mice (79), and

markedly elevated levels of IL-1 are found in
the circulation associated with prominent neutrophilia (79). The elevated levels of IL-1 are
lethal because blockade with IL-1Ra protects
these mice from death. The source of the IL1 in these mice is the neutrophil. When incubated with proteinase-3, cleavage of the IL-1
precursor is observed with molecular weights
of 25 and 15 kDa (79). In fact, the products of
proteinase-3 cleavage of the IL-1 precursor
are biologically active. In other studies, a molecular weight of active IL-1 at 2325 kDa has
been observed (83). Therefore, in inammatory
conditions such as urate crystal arthritis, which
is characterized by a prominent neutrophilic
inltration, proteinase-3 cleavage of extracellular IL-1 precursor likely takes place. Mice
decient in caspase-1 are not protected against
urate-induced inammation. Although IL-1Ra
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is effective in treating gout, IL-1Ra would be

equally effective in any diseases with extracellular processing of the precursor (101). The importance of extracellular processing of the IL1 precursor by serine proteases may explain, in
part, the anti-inammatory properties of alpha1-antitrypsin (102).

Effects in mice deficient in IL-1. After ten

years of continuous breeding, mice decient in
IL-1 exhibit no spontaneous disease. However, upon challenge, IL-1-decient mice exhibit specic differences from their wild-type
controls. The most dramatic is the response to
local inammation followed by a subcutaneous
injection of turpentine. Within the rst 24 h,
IL-1-decient mice injected with turpentine
do not manifest an acute-phase response, do
Table 4
not develop anorexia, and have no circulating

IL-6 and no fever (98, 103). These ndings
are consistent with those reported in the same
model using anti-IL-1R type I antibodies in
wild-type mice (103). IL-1-decient mice also
have reduced inammation following zymosaninduced peritonitis (104). Not unexpectedly,
given their lack of endogenous IL-1, IL-1decient mice have elevated febrile responses to
IL-1 and IL-1. In contrast, IL-1-decient
mice have nearly the same responses to LPS
as do wild-type mice (105). However, unlike wild-type mice, IL-1-decient mice injected with LPS have little or no expression
of leptin mRNA or protein (106). As shown
in Table 4, the data demonstrate that in the
mouse, IL-1 is critical for local and systemic
inammation.
Responses in IL-1-deficient mice
Disease model
532
Effects
LPS-induced fever
fever similar to wild-type or fever
LPS-induced leptin
circulating leptin
LPS-induced hypoglycemia
normoglycemia
LPS-induced shock lung
no effect on neutrophil inltration
LPS-induced coagulopathy
plasminogen activator inhibitor unchanged
disseminated Candida albicans
peritoneal neutrophils, superoxide production
Zymosan peritonitis
inammation, mortality, and IL-6 and chemokines
Turpentine-induced inammation
fever, IL-6, SAA, cortisone, COX-2
C-protein-induced myositis
disease severity
IL-1-induced fever
fever, cytokines
B16 melanoma
hepatic metastasis, VCAM-1
Brain ischemia-reperfusion
neuronal death
Model of myasthenia gravis
disease development
Systemic lupus erythematosus
anti-dsDNA, disease severity
Collagen-induced arthritis
disease severity, CD40 ligand, OX40
Fas-expressing tumors
neutrophil inltration
Turpentine-induced coagulopathy
plasminogen activator inhibitor
Contact hypersensitivity
Langerhans cell activation
Steady-state levels of p65 (NF-B)
levels and nuclear translocation
Delayed-type hypersensitivity
sensitized CD4+ T cells, proliferation to antigen
Airway hypersensitivity to antigen
bronchoconstriction, IgG1 and IgE
Carcinogen-induced tumors
tumors, neutrophil inltration
Injury-induced astrogliosis
glial brillary acid protein
Meniscus model of osteoarthritis
damage to cartilage
VEGF-mediated neovascularization
hypoxia-inducible factor-1, VEGF, VEGFR-2
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Differences in carcinogenesis between IL1 and IL-1-deficient mice. Mice decient

in IL-1 were compared with mice decient
in IL-1 in the microenvironment after chemical carcinogenesis (58). On the one hand, in
IL-1-decient mice tumors developed slower
or did not develop in some mice. A deciency
in IL-1, on the other hand, did not impair
tumor development compared with wild-type
mice injected with the same carcinogen. In IL1Ra-decient mice, tumor development was
the most rapid. A leukocyte inltrate was found
at the site of carcinogen injection. The neutrophilic inltrate was almost absent in IL1-decient mice, whereas in IL-1Ra-decient
mice, a dense neutrophilic inltrate was observed. In wild-type mice, the leukocytic inltrate was sparse, and the inltrate that was observed in IL-1-decient mice was similar to
that of control mice. These ndings may reect the fact that IL-1 is secreted into the
microenvironment, resulting in the emigration
of monocytes and neutrophils, whereas IL-1
that remains cell associated is less likely to affect the microenvironment. The relationship
of neutrophil-derived oxygen radicals and carcinogenesis is well established.
IL-1Ra (IL-1F3)
The structural analysis of the IL-1RI/IL1Ra complex. X-ray crystallography reveals
that IL-1 has two sites of binding to IL-1RI.
IL-1Ra also has two binding sites, which are
similar to those of IL-1. However, one of the
binding sites of IL-1Ra binds to IL-1RI with a
high afnity such that the second binding site
is not available to recruit the IL-1RAcP. After binding of IL-1Ra to IL-1RI-bearing cells,
there was no phosphorylation of the epidermal growth factor receptor, a well-established
and sensitive assessment of IL-1 signal transduction. Overwhelming evidence that IL-1Ra
is a pure receptor antagonist comes from studies
of intravenous injection of IL-1Ra into healthy
humans. At doses 1,000,000-fold greater than
that of IL-1 or IL-1, IL-1Ra had no agonist
activity in humans.
Studies using IL-1Ra in animals. Because

IL-1Ra exhibits no species specicity, a large
body of data exists revealing a role for IL-1 in
animal models of disease. The effects of blocking IL-1 activity in various animal models have
been reviewed previously (107).
IL-1Ra (anakinra) treatment of autoinflammatory diseases. Table 2 lists several autoinammatory diseases that have been treated with
anakinra. In most cases, the responses have been
rapid and sustained with daily injections, but
disease activity returns upon cessation (12, 27,
108). IL-1 is highly injurious to the insulinproducing pancreatic beta cell (16). High
glucose concentrations induce the IL-1 production from human beta cells, resulting in
impaired insulin secretion, decreased cell proliferation, and beta cell death (109). In a
placebo-controlled trial in patients with type 2
diabetes, anakinra treatment for 13 weeks resulted in signicantly lower levels of glycated
hemoglobin level compared with the placebo
group (17). The blockade of IL-1 was also associated with lower levels of C-reactive protein
and IL-6. The benet of blocking IL-1 to protect the insulin-producing beta cells has been
conrmed in type 2 diabetic patients treated
with a monoclonal antibody to IL-1 (18).
Mice deficient in IL-1Ra. Mice decient in
IL-1Ra have low litter numbers and exhibit
growth retardation in adult life (110). These
animals also have elevated basal concentrations of plasma IL-6 and exhibit higher levels of hepatic acute-phase proteins compared
with those of wild-type control mice. The
most dramatic phenotype has been observed in
IL-1Ra-decient mice crossed into a BALB/c
background (56). In these mice, a chronic inammatory polyarthropathy develops spontaneously. The joints show prominent synovial
and periarticular inltration of inammatory
cells, osteoclast activation, and bone erosion.
The histological pattern is similar to that of
humans with rheumatoid arthritis. There are
elevated levels of rheumatoid factor and antidouble-stranded DNA antibodies. Steady-state
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levels of COX-2, IL-1RI, IL-1, IL-6, and

TNF- mRNA in the affected joints are also increased. IL-17 is required for IL-1Ra-decient
mice to develop the arthritis (50). The onset
of this autoimmune process also requires a genetic background favoring the Th2 response,
which produces antibodies rather than cytotoxic T cells in response to antigens. The immunologic stimulus likely occurs when either
an endogenous antigen or an antigen from the
intestinal ora triggers a Th2 response, which,
in the absence of endogenous IL-1Ra, results in
unopposed IL-1 activities.

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IL-18 (IL-1F4)
The discovery of IL-18 was made as an IFN-inducing cytokine in endotoxemic mice (111);
without IL-12 or IL-15, IL-18 does not induce
IFN-. A role for IL-18 in the Th17 response is
unclear at present. Mice injected with the combination of IL-18 plus IL-12 develop high levels
of IFN- and die with hypoglycemia, intestinal
inammation, and inanition (112). In leptindecient mice, IL-18 plus IL-12 induce acute
pancreatitis (113). Several human diseases are
associated with elevated production of IFN-
and IL-18. Diseases such as systemic lupus erythematosus, macrophage activation syndrome,
rheumatoid arthritis, type 1 diabetes, Crohns
disease, psoriasis, and graft-versus-host disease
are thought to be mediated, in part, by IL-18.
Like IL-1, IL-18 is initially synthesized
as an inactive precursor (24 kDa) and requires
caspase-1 cleavage for processing into a mature molecule of 18 kDa (Figure 2). Following
an injection of endotoxin, caspase-1-decient
mice have signicantly lower levels of circulating IFN- compared with wild-type mice.
IL-12-induced IFN- is also caspase-1 dependent (114). In general, processing of the IL-18
precursor is caspase-1 dependent, but exceptions exist. For example, Fas ligand stimulation results in release of biologically active IL18 in caspase-1-decient murine macrophages
(115). As with IL-1 processing, processing of
the IL-18 precursor can be accomplished by
proteinase-3 (100).
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Dinarello
IL-18, hyperphagia, and the metabolic syndrome. There is another side to the biology
of IL-18. Whereas there is no constitutive gene
expression for IL-1 in freshly obtained human
peripheral blood mononuclear cells (PBMCs),
the same cells express constitutive mRNA for
IL-18 (116). In Western blot analysis from the
same cells, the IL-18 precursor was present, but
the IL-1 precursor was not. Similar observations have also been made in mice (116). These
ndings suggest that IL-18 may act as a regulator of homeostasis.
Starting at age 16 weeks, IL-18-decient
mice overeat, become obese, and exhibit lipid
abnormalities, increased atherosclerosis, insulin resistance, and diabetes mellitus reminiscent of the metabolic syndrome (59). The
higher body weight is attributed to enhanced
food intake, which starts to diverge from those
of wild-type animals at a relatively early age and
reaches values of 3040% higher than that of
wild-type mice. Others have observed similar
ndings (117). A striking nding was a doubling or more in adipose tissue in the decient
animals that was accompanied by fat deposition in the arterial walls. The insulin resistance
was corrected by exogenous recombinant IL18. Mice decient in IL-18 respond normally
to a challenge with exogenous leptin, suggesting that a unique mechanism is responsible for
the higher food intake in the IL-18-decient
animals.
IL-18-binding protein. The discovery of the
IL-18BP took place during the search for the
soluble receptors for IL-18 in human urine (9).
IL-18BP is a constitutively secreted protein,
with exceptional afnity to IL-18 (400 pM)
(see Figure 3). There is limited amino acid
sequence homology between IL-18BP and
cell surface IL-18 receptors; IL-18BP lacks a
transmembrane domain and contains only one
Ig-like domain (118). IL-18BP is a specic inhibitor of IL-18, neutralizing IL-18 activities.
Present in the serum of healthy humans at a 20fold molar excess compared with IL-18 (119),
IL-18BP may contribute to a default mechanism by which a Th1 response to foreign

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organisms is blunted in order to reduce triggering an autoimmune response to a routine

infection. A clinical preparation of human IL18BP has been shown to be safe in patients
(120).
Natural neutralization of human IL-18 by
IL-18BP takes place during a common viral
infection. In Molluscum contagiosum, characterized by raised but bland eruptions, there are
large numbers of viral particles in the epithelial cells of the skin, but histologically there
are few inammatory or immunologically active cells in or near the lesions. Clearly, the virus
fails to elicit an inammatory or immunological response. Amino acid similarity exists between human IL-18BP and a gene found in various members of the poxviruses, the greatest of
which is found to be expressed by Molluscum contagiosum (121). The ability of viral IL-18BP to
reduce the activity of mammalian IL-18 likely
explains the lack of inammatory and immune
cells in the infected and provides further evidence for the natural ability of IL-18BP to interfere with IL-18 activity.
IL-1F5
IL-1F5 shares 47% amino acid identity with IL1Ra and is expressed in human monocytes activated by LPS. From the gene sequence, the predicted amino acid sequence of IL-1F5 does not
have a leader peptide for secretion, which is in
sharp contrast to the IL-1Ra (IL-1F3). IL-1F5
failed to exhibit agonist activity using induction of IL-6 from broblasts, a well-described
biological property of IL-1 and IL-1 (122).
Furthermore, IL-1F5 did not block the IL1- or IL-1-induced IL-6- or IL-18-induced
production of IFN- (122). Therefore, IL-1F5
possesses neither IL-1- or IL-18-like agonist
activities nor the property to act as a receptor
antagonist for IL-1, despite its close amino acid
identity to IL-1Ra.
It appears, however, that IL-1F5 functions
as an anti-inammatory member of the IL-1
family. IL-1F5 induces IL-4, which can reduce IL-1 activity. The anti-inammatory effects of IL-1F5 include downregulating the re-
IL-18
IL-18BP
IL-18R
Neutralization
IL-18R
NF-B
Approximation
of cytoplasmic
Toll domains
IB
MyD88
Recruitment
of kinases
IRAK 14
IKK
TRAF-6
MAPK
IKK
p38 MAP
Nucleus
Figure 3
IL-18 signal transduction. The afnity of mature IL-18 for the IL-18R is low
(Kd = 50 nM) but increases 100-fold with a complex of IL-18R. Signal
transduction in IL-18 involves MyD88 and IL-1 receptorassociated kinases
(IRAKs). TNF receptorassociated factor (TRAF)-6 is also a part of IL-18
signaling. TRAF-6 is required for the phosphorylation of mitogen-activated
protein kinase (MAPK) p38.
sponses to IL-1 as well as LPS; in mice decient in IL-4, IL-1F5 is less effective as an
anti-inammatory cytokine (2). The ability of
IL-1F5 to dampen inammation is via its interaction with the SIGIRR, also known as Toll
IL-1 receptor-8 (TIR8). SIGIRR is an orphan
member of the IL-1 family of receptors, and in
mice decient in SIGIRR there is more inammation compared with wild-type control mice
(2).
IL-1F6
IL-1F6 is a proinammatory member of the
IL-1 family. The cytokine binds to the IL1R-related protein (IL-1Rrp2) as its ligandbinding chain and recruits IL-1RAcP to form
the heterodimer. High levels of IL-1F6 are
found in mouse embryonic tissues rich in epithelial cells (123). In humans, IL-1F6 is observed in keratinocytes but not in broblasts,
but it is thought to contribute to the inammation of psoriasis. Upon forming the heterodimer with IL-1Rrp2 and IL-1RAcP, IL1F6 activates NF-B similar to that of IL-1
(124). In addition to NF-B activation, IL-1F6
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also activates mitogen-activated protein kinase

(MAPK), JNK, and ERK1/2 (124).
IL-1F7

IL-1F7 is an anti-inflammatory cytokine.

Discovered by computational cloning, IL-1F7
is a seldom-studied member of the IL-1 family. IL-1F7s closest structural relative is IL-18.
There are ve splice variants of IL-1F7, and IL1F7b contains all but one exon (125). With the
sole exception of IL-1Ra, each member of the
IL-1 family, including IL-1F7, is rst synthesized as a precursor without a leader or signal
peptide. Although the recombinant form of IL1F7 is processed by caspase-1 in vitro (126), it is
unclear whether such processing results in secretion of the carboxyl terminal peptide in vivo.
When IL-1F7 is overexpressed in cell lines under various promoters, immunoprecipitates reveal the cytokine complexed with the IL-18 receptor chain (IL-18R) (126, 127). A second
study employed recombinant IL-1F7. In Biacore studies, IL-18R was immobilized to the
matrix, and binding of IL-1F7 was observed,
although with a lower afnity than that of IL18 (126). Compared with IL-18, recombinant
IL-1F7 does not induce IFN- in whole human blood cultures, in PBMCs, or in various
cell lines in the presence of IL-12 (126, 128).
Therefore, recombinant IL-1F7 lacks true agonist activity; an accessory receptor chain has
not been described. Nevertheless, when injected directly into murine tumors, adenovirus
expressing the IL-1F7 precursor reduces tumor
growth (129). Although recombinant IL-1F7
binds to immobilized IL-18R chain, IL-1F7 is
also not a receptor antagonist for IL-18 activity
(128).
The naturally occurring IL-18BP binds IL18 with a high afnity, thus neutralizing IL-18
activity in vitro and in vivo (9). Recombinant
IL-1F7 also binds to the IL-18BP (128), and
this binding may be due to the similarities of
IL-18BP to the third domain of the IL-18R
chain (130). At low concentrations of IL-18BP,
the presence of recombinant IL-1F7 further
reduces the inhibition of IL-18 (128), perhaps
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by forming a complex of IL-18BP with the IL18R chain and thus depriving the IL-18R
of its coreceptor. Support for this mechanism
comes from mice with collagen-induced arthritis and treated with IL-18BP. Increasing the
concentration of IL-18BP can worsen inammation (131). As discussed below, overexpression of IL-1F7 inhibits IL-1, TNF-, and
TLR production of cytokines. One explanation
is that high levels of IL-18BP bind IL-1F7 and
thus prevent its interaction with IL-18R. In
fact, in mice decient in IL-18R, there is increased inammation, whereas in mice decient
in IL-18 itself, there is less inammation (132).
In mice with EAE, a deciency in the IL-18R
results in the opposite outcome compared with
mice decient in IL-18 (133). The two studies
concluded that the IL-18R chain may bind
another ligand in addition to IL-18 and that
this ligand may be IL-1F7. Such a mechanism
of action would likely require a coreceptor, and
one candidate would be SIGIRR (7, 8).
In stable transfectants of human IL-1F7b
in mouse RAW macrophages stimulated with
LPS, levels of TNF-, IL-1, and IL-6 as
well as the chemokine CXCL2 (MIP-2) were
substantially reduced (3098%) compared
with LPS-stimulated stable transfectants with
the empty plasmid (1, 134). Reductions in
proinammatory cytokines (IL-1, IL-1,
IL-6, IL-8, TNF-) were demonstrated in
human THP-1 monocytes/macrophages transfected with IL-1F7 and stimulated with LPS
(134); similar reductions were also observed in
transfected human epithelial A549 cells stimulated with IL-1 (134). To prove causality,
endogenous IL-1F7 was reduced by siRNA in
TLR agonist-stimulated PBMCs from seven
donors. With reduced levels of IL-1F7 in these
cells, there was a dose-dependent increase up
to threefold in 13 proinammatory mediators,
among which were IL-1, IL-1, IL-6, TNF, and GM-CSF (134). Intracellularly, IL-1F7
markedly reduced by up to 75% the activation
of several kinases (Stat1 through 4, p38MAPK,
c-Jun, and Hck). Therefore, it appears that
IL-1F7 is a naturally occurring inhibitor of the
innate immune response.

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Using two variants of green uorescent protein fused to human IL-1F7b in stably expressed
RAW macrophages, only the postcleavage mature form of the IL-1F7b precursor, but not
the N-terminal propiece, specically translocated to the nucleus following LPS stimulation
(1). Similar to IL-1, IL-18, and IL-33, the IL1F7 precursor is cleaved by caspase-1 to generate the mature cytokine (126). Indeed, a specic
caspase-1 inhibitor reduced nuclear binding of
IL-1F7b. These results demonstrate that IL1F7b translocates to the nucleus after caspase1 processing and may act as a transcriptional
modulator reducing the production of LPSstimulated proinammatory cytokines, consistent with IL-1F7b being an anti-inammatory
member of the IL-1 family.
IL-1F8
The receptor for IL-1F8 is IL-1Rrp2 and is
expressed on human synovial broblasts and
human articular chondrocytes. In response to
stimulation by recombinant IL-1F8, there is
increased production of proinammatory mediators (135). Although IL-1F8 steady-state
mRNA is constitutive in chondrocytes, the
cytokine is inducible by IL-1 in synovial
broblasts. Circulating levels of IL-1F8 in patients with rheumatoid arthritis, osteoarthritis, or septic shock were similar to those in
healthy subjects. It is unclear to what extent
IL-1F8 plays a role in joint disease, although
constitutive expression in primary chondrocytes may indicate a role for the cytokine in
osteoarthritis.
IL-1F9
IL-1F9 is constitutively expressed primarily in
the placenta and the squamous epithelium of
the esophagus. The three-dimensional folding
of IL-1F9 is similar to that of IL-1Ra; nevertheless, IL-1F9 is a proinammatory cytokine
binding to IL-1Rrp2 and recruiting the IL1RAcP. IL-1F9 triggers the same kinase cascade
and NF-B as IL-1F6 (see above).
IL-1F10
IL-1F10 shares 37% amino acid identity with
the IL-1Ra and a similar three-dimensional
structure (136). This cytokine is secreted from
cells and is expressed in human skin, spleen,
and tonsil. To date, recombinant IL-1F10 has
been shown to bind to the isolated extracellular domains of IL-1RI, but it is unclear whether
IL-1F10 binds to complete cell surfacebound
IL-1 receptors. Although these data suggest
that IL-1F10 is likely to be a receptor antagonist (137), compared with IL-1Ra, its role in
health and disease remains unclear.
IL-33 (IL-1F11)
IL-1F11 is also known as IL-33. Although given
the newest name in the IL-1 family, the existence of this member was predicted 16 years ago
as the ligand for the orphan receptor T1/ST2.
ST2 is also termed the IL-33 receptor chain
(IL-33R), and recombinant IL-33 binds to
and activates ST2. From studies using soluble
forms of ST2 or antibodies to ST2, we know
that the ligand (now known as IL-33) drives T
helper type 2 (Th2) responses (3). In 1994, the
receptor termed ST2 was rst reported as regulated by the estrogen-inducible transcription
factor Fos (138). The ST2 receptor was similar
to the IL-1RI and IL-18R in that ST2 is composed of three extracellular Ig domains and an
intracellular Toll domain. During the search for
its cognate ligand, investigators assumed that
its ligand would be a member of the IL-1 family. Thus, the properties of recombinant IL33 recapitulate much of the existing data that
ST2 promotes Th2 type responses. Like IL-1
(IL-1 and IL-1) binding to the IL-1RI,
IL-33 forms a heterodimeric complex with
IL-1RAcP for signal transduction (37, 139).
IL-33 gains considerable legitimacy as a member of the IL-1 ligand family because processing of the IL-33 precursor is accomplished
by caspase-1 (3), similar to IL-1 and IL-18.
Lack of processing of IL-33 into an active cytokine may contribute to the protection afforded caspase-1-decient mice.
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However, there is another side to IL-33.

Although IL-33 binds to its specic surface
receptor, IL-33 is identical to a nuclear factor
dominantly expressed in high endothelial
venules (HEV) (5). This nuclear factor is
termed NF-HEV. In fact, IL-33s binding to
DNA and acting as a nuclear factor is similar to
IL-1s functioning as a nuclear factor (4, 140).
Thus, IL-33 is one of a growing number of
cytokines that both signal via a classic receptor
trigger and function as a nuclear factor in
regulating transcription. These cytokines
presently include IL-33 (5), IL-1 (4), IL-16
(141), and high mobility factor B (142).
There was no dearth of studies on ST2
tissue-specic localization, regulation of its expression, and effects in transgenic mice overexpressing ST2 or on deletion, neutralization,
and antibody cross-linking of ST2. Elevated
levels of the soluble form of ST2 were present
in the circulation of patients with various inammatory diseases, and exogenous administration of pharmacologic doses of soluble
ST2 neutralized the putative ligand and reduced inammation (143). Furthermore, several studies suggested that whatever the ligand
for this orphan receptor, it was playing a role
in allergic-type diseases, given that activation
of ST2 was uniquely driving Th2 responses.
Structurally, IL-33 is closest to IL-18, rather
than IL-1. The dominant property of IL-33
is the induction of IL-4, IL-5, and IL-13 as
well as properties anticipated for a Th2-type
cytokine. Diseases thought to be due to increased immunoglobulin production may also
be related to IL-33. IL-33 induces the production of IL-6, IL-1, and PGE from mast
cells.
Mice injected with human IL-33 exhibit impressive pathological changes in the arterial
walls, lungs, and intestinal tissues (3). Of particular relevance to the concept that IL-33 drives
a Th2 response, eosinophilic inltration was a
prominent nding in the lung. Although the interpretation of in vivo effects following the administration of an exogenous cytokine should
be conservative, the ndings are clearly consistent with IL-33 being a proinammatory ligand

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of the IL-1 receptor family. Even before the

ability to test IL-33-mediated activation, others had reported that neutralization of the putative ST2 ligand using soluble ST2 markedly reduced joint inammation, synovial hyperplasia,
and joint erosion when given in the therapeutic phase of collagen-induced arthritis in mice
(143). Moreover, organs with high numbers of
mast cells appear to undergo dramatic changes
upon injection of IL-33 into mice. Consistent
with a role in allergic diseases, IL-33 induces in
vivo the cytokines IL-5 and IL-13, known contributors to allergic diseases. Mice decient in
ST2 do not develop a Th2 response to Schistosoma egg antigen.
How IL-33 favors the Th2 response remains
unclear. Similar to IL-1, IL-33 induces IL6, which is an adjuvant for antibody production. IL-33 induction of IL-6 is prevented by a
blocking antibody to IL-1RAcP (37). IL-33 initiates signal transduction via activation of NFB, which is typical of IL-1, IL-1, and IL18 (3), but other studies have shown that antibody cross-linking of ST2 does not result in
activation of NF-B but rather of AP-1. There
are also studies that indicate that IL-33 has
anti-inammatory properties by inhibiting angiotensin IIinduced phosphorylation of IB
in cardiac broblasts (144). ST2 can sequester
TLR adaptor molecules such as MyD88 and
Mal (145).
One of the more challenging aspects of IL33s ability to act as a Th2 cytokine is its role
as an antagonist in the ApoE-decient mouse
model of atherosclerosis. In this model, arterial wall plaques of mice on a high-fat diet contain IL-33 and ST2. In mice treated with IL33, the atherosclerotic plaques were markedly
reduced (146). IL-33 treatment also increased
serum IgA and IgE, an expected response for a
switch from Th1 to Th2. In mice treated with
soluble ST2 to neutralize IL-33, the disease
was worse (146). These studies are inconsistent, however, with the role of caspase-1 as required for processing of IL-33 because the soluble ST2 neutralizes mature IL-33. Also, these
studies are inconsistent with a role for IL-33 as
NF-HEV (5).
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IL-1 Receptor Family

The IL-1 receptor family encodes ten members, some of which remain orphan receptors.
As shown in Figure 4, most belong to the group
containing three IgG-like segments for the
extracellular domain of the receptor. Table 5
summarizes the IL-1 receptor family and their
functions (147). IL-1R1, IL-1R2, and IL-1R3
are the bona de receptors for IL-1 and IL1. IL-1R4, also known as ST2, is no longer
an orphan receptor because IL-33 binds to this
receptor (3). Before the identication of IL-33
as the ligand for ST2, a number of studies had
examined the function, distribution, and gene
regulation of this receptor, particularly on mast
cells (148). IL-1R5 was formerly an orphan receptor termed IL-1R related protein-1 (149),
but it was subsequently discovered to be the
ligand-binding () chain of the IL-18 receptor
(150), now termed IL-18R.
The IL-1Rrp2 is the receptor for the agonists IL-1F6, IL-1F8, and IL-1F9, but it is also
the receptor for IL-1F5, which is the antagonist for IL-1F9 (123, 147). IL-1R7, formerly
the nonligand-binding chain of the IL-18 receptor termed IL-1RAcPL (151), is now named
IL-18R chain. Similar to the IL-1RAcP, the
IL-18R is essential for IL-18 signal transduction (151, 152).
Two members of the IL-1 receptor family are particularly unique in that they are
found on the X chromosome. These are IL1R8 and IL-1R9, both homologous to the
Table 5
Ligandbinding
() chain
IL-1RI
IL-18R
ST2 (IL-33R)
TIGIRR-1
TIGIRR-2
IL-1Rrp2
Coreceptor
() chain
Decoy
receptor
IL-1RII
IL-1RAcP
IL-18R
SIGIRR
Toll-like
domain
Figure 4
IL-1 family of receptors.
IL-1RAcP and IL-18R (see Table 5). IL1R9 is highly homologous to IL-1R8 and both
are termed three Ig IL-1-related receptors
(TIGIRR). Both forms have no known ligands,
and receptors are found in the fetal brain. In
fact, nonoverlapping deletions and a nonsense
mutation in the IL-1r8 were found in patients
with cognitive impairment (153) in which expression in the adult hippocampal area may play
a role in memory or learning. The cytoplasmic
domains of IL-1R8 and IL-1R9 are longer than
the other accessory chains. The IL-1R9 may
function as a negative receptor, as was shown
in cells overexpressing this receptor as well as
the IL-1RI and IL-1RAcP in which IL-1 signaling was blocked with a specic antibody to
the IL-1RAcP. In the presence of the antibody,
The IL-1 receptor family
Name
Designation1
Ligands
Coreceptor
IL-1RI
IL-1R1
IL-1, IL-1, IL-1Ra
IL-1RAcP (IL-1R3)
IL-1RII
IL-1R2
IL-1, IL-1 precursor
IL-1RAcP (IL-1R3)
ST2/Fit-1
IL-1 R4 (IL-33R)
IL-33
IL-1RAcP (IL-1R3)
IL-18R
IL-1R5
IL-18, IL-1F7
IL-18R (IL-1R7)
IL-1Rrp-2
IL-1R6
IL-1F6, IL-1F8, IL-1F9
IL-1RAcP (IL-1R3)
TIGIRR-2/IL-1RAPL
IL-1R8
unknown
unknown
TIGIRR-1
IL-1R9
unknown
unknown
SIGIRR
TIR8
unknown
unknown
IL-1 receptor family members IL-1R3 (IL-1RAcP) and IL-1F7 (IL-18R) are coreceptors and require binding to an IL-1
family ligand plus a ligand-binding chain.
Inhibitory
receptor
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IL-1-induced luciferase was suppressed, suggesting that a possible complex of the type I
receptor with IL-1 plus IL-1R9 results in a
negative signal (154).
Single Ig IL-1 Related Receptor

SIGIRR is a negative regulator of both IL-1

and IL-1 activities but also of TLR agonists.
Although there is only a single IgG domain
for the extracellular segment, the cytoplasmic
domain contains a Toll domain and has the
longest cytoplasmic domain of all the members
of the IL-1 receptor family (Figure 4). Initially,
SIGIRR was thought to be expressed primarily
in kidney, lung, and the gastrointestinal tract,
primarily in resting epithelial cells. However,
SIGIRR is also expressed in human monocytes
and mouse macrophages upon the stresses associated with infection and transient hypoxia.
Dendritic cells also express SIGIRR (8). In a
study of patients resuscitated from cardiac arrest, the peripheral monocytes displayed increased steady-state levels of SIGIRR, which
were associated with increased gene expression
for the anti-inammatory cytokine IL-10 and
decreased expression for TNF-. In microglia
of mice infected with murine leukemia virus, a
gene array of 14,000 genes revealed that only
three genes were differentially expressed between the virulent and nonvirulent strains of
the viruses, and one of these genes coded for
SIGIRR (155).
With overexpression of SIGIRR in the form
of a chimeric molecule with IL-1RAcP, suppression of IL-1-driven NF-B was observed.
SIGIRR inhibition of IL-1-driven NF-B does
not require the presence of the extracellular domain of SIGIRR. The complex of IL-1 with
IL-1RAcP activates NF-B, but in the presence of SIGIRR there is suppression of the
response. In another study, inhibition of IL-1
activity required the extracellular single Ig
domain of SIGIRR (156). The mechanism for
suppression of the IL-1 responses in cells overexpressing SIGIRR is one of competitive inhibition of MyD88, such that there is no activa-
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tion of IL-1 receptorassociated kinase (IRAK)

or TNF receptor-associated factor (TRAF)-6
(156). The inhibition of MyD88, IRAK, and
TRAF-6 by SIGIRR is not due to the formation of a complex with IL-1RAcP or IL-1RI.
Overexpression of SIGIRR results in inhibition
of LPS and IL-1 activities, whereas mice decient in SIGIRR exhibit heightened inammation. Mice decient in SIGIRR develop a more
severe disease in response to LPS or chronic
colitis (7, 8). Overexpression of SIGIRR in 293
cells inhibits both IL-1- and IL-18-induced
NF-B reporter activity but not IFN- activity (7). Splenocytes from mice decient in
SIGIRR produce several-fold greater levels of
the mouse chemokines KC and CXCL2 (MIP2) and CXCL10 (IP-10) following LPS. In a
model of live Pseudomonas keratitis, a blocking
antibody to SIGIRR resulted in increased bacterial counts and increased steady-state mRNA
levels of IL-1, IL-18, and IL-18 (157). Overexpression of SIGIRR in macrophages resulted in decreased mRNA levels for IL1RI, IFN-, IL-12, and IL-18. This SIGIRR downregulates the responses to IL-1 and
TLR4.
IL-1 Receptor Type I

In crystallization studies, IL-1RI undergoes a
conformational change when binding IL-1
and allows the IL-1RAcP to form the heterodimer (Figure 5). The cytoplasmic domain
of IL-1RI is unique in that it contains homology to the Drosophila Toll protein, termed
the TIR domain. The TIR domain is also
found in the cytoplasmic domains of each TLR.
The TIR domains of IL-1RI and also of the
coreceptor IL-1RAcP are necessary for signal
transduction. Although most cells express IL1RI constitutively, expression of IL-1RAcP is
not constitutive in some cells. A small synthetic peptide (RYTVELA) derived from the
sequence of the third domain of the IL-1RAcP
was tested for blocking IL-1 activity. This peptide, known as 101.10, blocks the functions
of the IL-1RI in human, mouse, and rat cells

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(158) and has no effect in mice decient in IL1RI. Active at 1 nM, 101.10 reduced inammatory colitis in the rat and contact dermatitis.
The location of the peptide is the site of interactive loops between IL-1RAcP and the IL1RI. When present, the peptide functions as an
allosteric, noncompetitive antagonist, inhibiting some but not all functions of the IL-1RI
(158). This property of allosteric antagonism
has been observed for the leukocyte function
associated antigen-1 (LFA-1) integrin where
a peptide binds to an allosteric site and inhibits only some of the properties of LFA-1
(159).
Studies in IL-1RI and

IL-1RAcP-Deficient Mice
The most proximal (5 ) promoter region of the
IL-1RI lacks a TATA or CAAT box and bears a
striking similarity to the promoters of housekeeping genes rather than highly regulated
genes (160). Phorbol esters, PGE2, dexamethasone, epidermal growth factor, IL-2, and IL-4
increase surface expression of IL-1RI. Part of
the immunosuppressive properties of TGF-
may be due to downregulation of the IL-1RI
on T cells.
Mice decient in IL-1RI develop normally
and exhibit no particular phenotype. However, IL-1RI-decient mice exhibit an attenuated inammatory response to sterile abscesses
compared with wild-type mice. Delayed-type
hypersensitivity responses are also reduced in
IL-1RI-decient mice. IL-17 production requires IL-1RI on T cells (42). Not unexpectedly, IL-1RI-decient mice are susceptible to
infection with Listeria monocytogenes. Lymphocytes from IL-1RI-decient mice with major
cutaneous leishmanial infection produce more
IL-4 and IL-10, but less IFN-, than those from
wild-type mice. Cells decient in IL-1RAcP
have normal binding of IL-1 and IL-1Ra to
the IL-1RI but a 70% reduction in binding of
IL-1 (161). In these cells, there is no biological response to IL-1 despite binding of IL-1
to the type I receptor.
sIL-1RII
14
15
IL-1RII
1
IL-1RI
IL-1
IL-1RII + IL-1RAcP
IL-1RII + IL-1RAcP
2
13
IL-1RAcP
16
TAK1 TAB1 TAB2
3
Approximation
of cytoplasmic
Toll domains
4 MyD88
TRAF-6
No signal
*IRAK-1
No signal
Tollip
TAK1 TAB1 TAB2
*IRAK-4
Recruitment
of kinases
*IRAK-1
*IRAK-2
TRAF-6 6
TRAF-6
*TAK1
*IKK
9
p38 MAP
12
JNK
*IB
10
NF-B
11
Nucleus
Figure 5
IL-1 signal transduction and decoy receptors. IL-1 binding to the IL-1RI (1)
recruits the IL-1RAcP (2) to form a heterodimeric receptor (1+2). The
cytoplasmic Toll domains on each receptor chain approximate (3). MyD88 and
Tollip are recruited (4). MyD88 binding to the cytoplasmic domains triggers
the phosphorylations of the IL-1 receptorassociated kinases IRAK-4, IRAK-2,
and IRAK-1 (5). TRAF-6 is recruited (6). Phosphorylated IRAK-1 and TRAF-6
migrate to the membrane and associate with TAK1 (TGF--activated kinase 1),
TAK1-binding protein (TAB)-1, and TAB2 (7). The complex of TAK1, TAB1,
TAB2, and TRAF-6 migrates to the cytosol, where TAK1 is phosphorylated
following the ubiquitination of TRAF-6 (8). Phosphorylated TAK1 activates
IKK (9), and phosphorylated IKK phosphorylates IB (10). Phosphorylated
IB degrades, releasing NF-B, which enters the nucleus (11). In addition to
the phosphorylation of IKK, TAK1 also activates mitogen-activated protein
kinase (MAPK) p38 and JNK (12). On the surface of the cell, IL-1RII, a decoy
receptor, may also bind IL-1 (13), but this complex does not recruit
IL-1RAcP, and there is no signal. In the extracellular space, the extracellular
domains (soluble or sIL-1RII) of the IL-1RII bind IL-1 and neutralize its
activity (14). sIL-1RII can also bind IL-1 and form a complex with soluble
IL-1RAcP (15) or cell-bound IL-1RAcP (16). In the latter two complexes,
IL-1 is not available to bind to IL-1RI and therefore cannot transmit a signal.
541
ANRV371-IY27-19
ARI
18 February 2009
17:10
IL-1R Type II

As reported by Colotta et al. (162), IL-1RII is

a decoy receptor. As shown in Figures 4 and
5, the short cytoplasmic domain is unable to
initiate signal transduction because there is no
TIR domain. Therefore, IL-1RII captures IL1 without signaling. Intracellularly, the IL-1RII
associates with the IL-1 precursor (65). Genes
in the pox family of viruses encode for a protein with a high homology to the extracellular
(soluble) domains of the receptor (sIL-1RII). In
humans, sIL-1RII is released from the cell surface by a protease; sIL-1RII has a particularly
high afnity for mature IL-1 and therefore
functions as a naturally occurring neutralization mechanism for IL-1.
IL-1 binding to the sIL-1RII is nearly irreversible. The IL-1 precursor also preferentially binds to sIL-1RII. A more efcient function of the type II receptor is to form a trimeric
complex of the IL-1 with sIL-1RII and the
IL-1RAcP chain (163). This mechanism serves
to deprive the cell of both IL-1 as well as a

functional receptor accessory chain (reviewed
in 164). As shown in Figure 5, sIL-1RAcP
forms complexes on the cell surface of IL-1
bound to type II receptors and accounts for
the ability of sIL-1RAcP to reduce B lymphocyte activation (165). sIL-1RAcP inhibits IL1-induced NF-B activity in B cells but not in
T cells, whereas IL-1Ra inhibited IL-1 in both
cell types (166).
sIL-1RI
The administration of the extracellular domain
of the type I receptor (sIL-1RI) has been used in
models of inammatory and autoimmune disease, where a reduction in disease severity is
reported. However, in humans, sIL-1RI acts as
a carrier for IL-1, and disease activity in patients with rheumatoid arthritis worsens (167).
In mice, intravenous injection of sIL-1RI alone
induced a rapid increase in circulating IL-1,
but not of TNF- or IL-1 (168).
DISCLOSURE STATEMENT
The author is not aware of any afliations, memberships, funding, or nancial holdings that might
be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
These studies are supported by NIH Grant AI 15614. The author thanks Thomas MandrupPoulsen, Marc Y. Donath, Philip Buer, Anna Rubartelli, and Diana Boraschi for helpful
discussions.
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Annual Review of
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Contents
Volume 27, 2009
Frontispiece
Marc Feldmann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x
Translating Molecular Insights in Autoimmunity into Effective
Therapy
Marc Feldmann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1
Structural Biology of Shared Cytokine Receptors
Xinquan Wang, Patrick Lupardus, Sherry L. LaPorte,
and K. Christopher Garcia p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29
Immunity to Respiratory Viruses
Jacob E. Kohlmeier and David L. Woodland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 61
Immune Therapy for Cancer
Michael Dougan and Glenn Dranoff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 83
Microglial Physiology: Unique Stimuli, Specialized Responses
Richard M. Ransohoff and V. Hugh Perry p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p119
The Liver as a Lymphoid Organ
Ian Nicholas Crispe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p147
Immune and Inammatory Mechanisms of Atherosclerosis
Elena Galkina and Klaus Ley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p165
Primary B Cell Immunodeciencies: Comparisons and Contrasts
Mary Ellen Conley, A. Kerry Dobbs, Dana M. Farmer, Sebnem Kilic,
Kenneth Paris, Soa Grigoriadou, Elaine Coustan-Smith, Vanessa Howard,
and Dario Campana p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p199
The Inammasomes: Guardians of the Body
Fabio Martinon, Annick Mayor, and Jrg Tschopp p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p229
Human Marginal Zone B Cells
Jean-Claude Weill, Sandra Weller, and Claude-Agn`es Reynaud p p p p p p p p p p p p p p p p p p p p p p267
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Aire
Diane Mathis and Christophe Benoist p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p287
Regulatory Lymphocytes and Intestinal Inammation
Ana Izcue, Janine L. Coombes, and Fiona Powrie p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p313
The Ins and Outs of Leukocyte Integrin Signaling
Clare L. Abram and Clifford A. Lowell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p339

Recent Advances in the Genetics of Autoimmune Disease

Peter K. Gregersen and Lina M. Olsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p363
Cell-Mediated Immune Responses in Tuberculosis
Andrea M. Cooper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p393
Enhancing Immunity Through Autophagy
Christian Munz
p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p423
Alternative Activation of Macrophages: An Immunologic Functional
Perspective
Fernando O. Martinez, Laura Helming, and Siamon Gordon p p p p p p p p p p p p p p p p p p p p p p p p451
IL-17 and Th17 Cells
Thomas Korn, Estelle Bettelli, Mohamed Oukka, and Vijay K. Kuchroo p p p p p p p p p p p p p p485
Immunological and Inammatory Functions of the Interleukin-1
Family
Charles A. Dinarello p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p519
Regulatory T Cells in the Control of Host-Microorganism Interactions
Yasmine Belkaid and Kristin Tarbell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p551
T Cell Activation
Jennifer E. Smith-Garvin, Gary A. Koretzky, and Martha S. Jordan p p p p p p p p p p p p p p p591
Horror Autoinammaticus: The Molecular Pathophysiology of
Autoinammatory Disease
Seth L. Masters, Anna Simon, Ivona Aksentijevich, and Daniel L. Kastner p p p p p p p p p621
Blood Monocytes: Development, Heterogeneity, and Relationship
with Dendritic Cells
Cedric Auffray, Michael H. Sieweke, and Frederic Geissmann p p p p p p p p p p p p p p p p p p p p p p p p669
Regulation and Function of NF-B Transcription Factors in the
Immune System
Sivakumar Vallabhapurapu and Michael Karin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p693
vi
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cytokine, host defense, caspase-1, autoinammatory, inammasome

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c 2009 by Annual Reviews.

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IL-1 decoy receptor

There are 11 members of the IL-1 family

IL-1 family members

IL-18; IFN--inducing factor

Receptor antagonist (?)

decoy receptor (6), the single Ig IL-1-related

Annu. Rev. Immunol. 2009.27:519-550. Downloaded from www.annualreviews.org

THE DIFFERENCE BETWEEN

disorder to understand better the underlying

Although nearly all autoimmune diseases have

Annu. Rev. Immunol. 2009.27:519-550. Downloaded from www.annualreviews.org

distinct MHC-associated haplotype susceptibilities, are progressive rather than periodic,

Familial Mediterranean fever

Responsive primarily to IL-1 blockade.

The pathological mechanism of increased

Specific therapies for blocking IL-1 activities

IL-1 and IL-1

IL-1 and IL-1

IL-1 and IL-1

IL-1 and IL-1, IL-33

IL-1 and IL-1

Annu. Rev. Immunol. 2009.27:519-550. Downloaded from www.annualreviews.org

rare conditions. One important criterion for

OVERVIEW OF THE IL-1 FAMILY

1 ng/kg results in high levels of IL-6 (reviewed

OVERVIEW OF THE IL-1 FAMILY

Annu. Rev. Immunol. 2009.27:519-550. Downloaded from www.annualreviews.org

IL-1 (IL-1 or IL-1) functions as a costimulator of T cell functions, primarily together

IL-1 and Th2 Immune Responses

IL-1 and B Cell Functions

IL-1 and Th17

Annu. Rev. Immunol. 2009.27:519-550. Downloaded from www.annualreviews.org

IL-18 Is Both a Th1 and Th2 Cytokine

DEFICIENCY IN IL-1 FAMILY

Annu. Rev. Immunol. 2009.27:519-550. Downloaded from www.annualreviews.org

PRO- AND ANTI-INFLAMMATORY

Annu. Rev. Immunol. 2009.27:519-550. Downloaded from www.annualreviews.org

the IL-1 precursor into a mature molecule.

www.annualreviews.org Functions of the IL-1 Family

turpentine, which induces a local inammatory response, wild-type and IL-1-decient

Annu. Rev. Immunol. 2009.27:519-550. Downloaded from www.annualreviews.org

Annu. Rev. Immunol. 2009.27:519-550. Downloaded from www.annualreviews.org

Procaspase-1 CARD CARD

Processing and secretion of IL-1 via the

CARD: caspaseactivating recruiting

Annu. Rev. Immunol. 2009.27:519-550. Downloaded from www.annualreviews.org

ASC: apoptosisassociated speck-like

caspase-1 occurs without a requirement for a

Annu. Rev. Immunol. 2009.27:519-550. Downloaded from www.annualreviews.org

Inactive IL-1 precursor (31 kDa)

Inactive IL-18 precursor (22 kDa)

Inactive IL-33 precursor (30 kDa)

Inactive IL-1F7 precursor (25 kDa)

Noncaspase-1 processing of IL-1.