of June 2, 2013.
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Comprise the IL-33 Receptor Complex
IL-1 Receptor Accessory Protein and ST2
Jochen Schmitz, Stefan Pflanz and Robert A. Kastelein
Alissa A. Chackerian, Elizabeth R. Oldham, Erin E. Murphy,
2007; 179:2551-2555; ;
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Copyright © 2007 by The American Association of
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The Journal of Immunology
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IL-1 Receptor Accessory Protein and ST2 Comprise the IL-33
Alissa A. Chackerian, Elizabeth R. Oldham, Erin E. Murphy, Jochen Schmitz, Stefan Pflanz,
and Robert A. Kastelein1
IL-33 (IL-1F11) is a recently described member of the IL-1 family of cytokines that stimulates the generation of cells,
cytokines, and Igs characteristic of a type 2 immune response. IL-33 mediates signal transduction through ST2, a receptor
expressed on Th2 and mast cells. In this study, we demonstrate that IL-33 and ST2 form a complex with IL-1R accessory
protein (IL-1RAcP), a signaling receptor subunit that is also a member of the IL-1R complex. Additionally, IL-1RAcP is
required for IL-33-induced in vivo effects, and IL-33-mediated signal transduction can be inhibited by dominant-negative
IL-1RAcP. The implications of this shared usage of IL-1RAcP by IL-1(? and ?) and IL-33 are discussed.
Immunology, 2007, 179: 2551–2555.
naturally occurring antagonists and decoy receptors exist to reg-
ulate the potent inflammatory effects exhibited by these cyto-
kines. The best characterized members of this family, IL-1 (?
and ?) and IL-18, are expressed as prodomain containing
polypeptide precursors which are proteolytically cleaved to
generate the active form of the cytokine. These cytokines re-
quire the usage of two receptor subunits: a primary ligand-bind-
ing receptor chain and a second receptor chain which does not
bind to the ligand by itself, but is required to mediate signal
transduction (reviewed in Ref. 1).
IL-33 was identified computationally based on a sequence pro-
file generated by compiling ?-trefoil structures of IL-1 family
members and fibroblast growth factor. Like IL-1 and IL-18, IL-33
can be proteolytically cleaved in vitro by caspase-1 to generate a
mature form of the protein. When administered i.p. to mice, IL-33
has broad proinflammatory effects, inducing eosinophilia, spleno-
megaly, goblet cell hyperplasia and mucous production at mucosal
surfaces, and increased serum levels of IL-5 and IgE (2). Based on
these in vivo effects, IL-33 is likely to be involved in Th2-medi-
ated immune responses, including asthma, allergy, or parasitic hel-
minth infections. ST2, which is expressed on Th2 and mast cells
and is highly homologous to the ligand-binding subunits of the
IL-1 and IL-18 receptor complexes, was shown to be one compo-
nent of the IL-33R complex. On cells that express ST2, the pres-
ence of IL-33 leads to activation of a signaling pathway involving
MyD88 and NF-?B (2).
To understand the precise role of IL-33 and ST2 in the immune
response, it is necessary to identify the second component of the
IL-33R complex. The most prominent members of the IL-1 family,
The Journal of
nterleukin-33 is the 11th described member of the IL-1
family of cytokines. IL-1 family members share a common
?-trefoil structure and are highly proinflammatory. Several
IL-1 and IL-18, do not share usage of receptor subunits. However,
three more recently discovered IL-1 family members (IL-1F6, IL-
1F8, and IL-1F9) have been shown to use the second component
of the IL-1R complex, the IL-1R accessory protein (IL-1RAcP)2
(3). IL-1RAcP is necessary for IL-1? and IL-1?-mediated signal
transduction, but is unable to bind to these cytokines by itself
(4–8). We asked whether IL-1RAcP is also involved in IL-33
signaling. We show that IL-1RAcP?/?mice and polarized Th2
cells from IL-1RAcP?/?mice do not respond to IL-33 adminis-
tration. Additionally, we can detect a ST2/IL-33/IL-1RAcP com-
plex by ELISA. Finally, we show that dominant-negative (dn) IL-
1RAcP can inhibit IL-33-mediated signaling. These results clearly
show that IL-1RAcP is a member of the IL-33 signaling receptor
Materials and Methods
IL-1RAcP?/?mice (on a mixed C57BL/6 and 129Sv background) were
purchased from The Jackson Laboratory and bred at this institution.
Wild-type (WT) B6.129SF2/J mice were purchased from The Jackson
Laboratory. In some experiments, WT mice came from an internally
produced mixed C57BL/6–129Sv colony. Mice were i.p. injected with
2 ?g of recombinant human or murine IL-33 (produced as described
previously; Ref. 2) or saline daily for 6 days and sacrificed on day 7. All
animal studies were reviewed and approved by the DNAX Animal Care
and Use Committee.
Sample preparation and analysis
The percentage of eosinophils was determined by counting ?300 leuko-
cytes from smears of tail blood. Serum cytokines were quantified by mul-
tiplex immunoassay using the 22-Plex Mouse Cytokine kit (Linco Re-
search). Serum IgE was quantified with a mouse IgE ELISA set (BD
Biosciences). Gene expression was analyzed by RT-PCR of RNA prepared
from snap-frozen tissue as previously described (2). The ST2 primer used
detects message for both the soluble and membrane-bound forms of this
receptor. For histology, formalin-fixed, paraffin-embedded tissue was sec-
tioned and stained via periodic-acid Schiff.
CD4?cells were isolated from WT and IL-1RAcP?/?spleen and periph-
eral lymph nodes using the MACS CD4?T cell isolation kit (Miltenyi
Discovery Research, Schering-Plough Biopharma (formerly DNAX Research), Palo
Alto, CA 94304
Received for publication March 22, 2007. Accepted for publication June 11, 2007.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
1Address correspondence and reprint requests to Dr. Robert A. Kastelein, Discovery
Research, Schering-Plough Biopharma (formerly DNAX Research), 901 California
Avenue, Palo Alto, CA 94304. E-mail address: firstname.lastname@example.org
2Abbreviations used in this paper: IL-1RAcP, IL-1R accessory protein; dn, dominant
negative; WT, wild type; TIR, Toll/IL-1R.
Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00
The Journal of Immunology
by guest on June 2, 2013
Biotec), and cultured for 5 days on anti-CD3-coated plates in the presence
of 5 ng/ml IL-2, 10 ng/ml IL-4, 10 ?g/ml anti-IFN-?, and 1 ?g/ml anti-
CD28. Cells were washed and cultured for 3 days in medium containing
IL-2, washed again, and incubated with 5 ng/ml IL-2 ? 10 ?g/ml anti-ST2
(MD Biosciences) and 50 ng/ml IL-33. Supernatants were harvested after
20 h and cytokines were measured by multiplex immunoassay.
Receptor-ligand complex ELISA
A total of 3 ?g/ml murine ST2-Fc or IL-1R1-Fc fusion proteins (R&D
Systems) in PBS were coated overnight onto MaxiSorp plates (Nunc). Af-
ter washing, plates were incubated with 3 ?g/ml recombinant his6-tagged
murine IL-1RAcP and increasing concentrations of murine IL-33 or IL-1?
in PBS/1% BSA/0.05% Tween 20 for 1.5 h. Plates were washed and
incubated with anti-his6-peroxidase (Roche Diagnostics) for 1 h, washed
again, developed with tetramethylbenzidine peroxidase substrate (KPL),
stopped with H2PO4, and read on a plate reader at 450–570 nm.
HEK293FT cells (Invitrogen Life Technologies), which endogenously ex-
press human IL-1R1 and IL-1RAcP, were transfected with 3 ?g of a NF-
?B-driven reporter gene construct (pNF-?B-hrGFP; Stratagene), increasing
amounts of cMyc-tagged murine IL-1RAcP dn construct (with a stop
codon inserted before the Toll/IL-1R (TIR) domain), and 1 ?g of a plasmid
encoding murine ST2 (for cells stimulated with IL-33). Twenty-four hours
posttransfection, cells were stimulated with 20 ng/ml murine IL-1? (R&D
Systems) or murine IL-33 for 24 h and then analyzed for GFP expression
Administration of IL-33 to mice has potent inflammatory effects,
including massive blood eosinophilia, increased IL-5 and IgE se-
rum levels, and goblet cell hyperplasia at mucosal surfaces (2). To
investigate the possibility that IL-1RAcP is important for these
effects, we administered IL-33 or saline to WT and IL-1RAcP?/?
mice. The results are quite clear. In all readouts examined, both
human and murine IL-33 induce robust responses in WT mice, but
there is a complete absence of response in the IL-1RAcP?/?mice
(Fig. 1). WT mice receiving IL-33 have enlarged spleens and
respond to IL-33 administration. WT and IL-
1RAcP?/?mice were given six daily injec-
tions of 2 ?g of IL-33 and sacrificed on day
7. A, Periodic-acid Schiff stain of the small
intestine showing the small intestinal villi
with prominent goblet cell hyperplasia in the
IL-33-treated WT animals. B, Serum IL-5
and IgE, and percent of total blood leuko-
cytes that are eosinophils. C, Gene expres-
sion in the lung. A similar pattern was seen
in the spleen. These results are representa-
tive of three experiments. Shown are the re-
sults with human IL-33. Murine IL-33 ad-
ministration yielded similar results. Mean ?
SEM, n ? 3–5 mice/group.
IL-1RAcP?/?mice do not
2552IL-1RAcP IS A MEMBER OF THE IL-33R COMPLEX
by guest on June 2, 2013
lymph nodes, while IL-1RAcP?/?mice treated with IL-33 look
identical with mice receiving saline (data not shown). Further anal-
ysis revealed that WT mice treated with IL-33 have increased lev-
els of IL-5 and IgE in the serum, blood eosinophilia, increased
message for IL-4, IL-5, IL-13, IL-6, ST2, and IL-17RB (IL-25R)
in the lung and spleen, and goblet cell hyperplasia in the small
intestine and upper airways of the lung (Fig. 1, and data not
shown). These results confirm that IL-33 is a potent activator of the
cells and cytokines involved in type 2 immune responses. Inter-
estingly, IL-33 can stimulate the expression of its own receptor,
ST2, as well as the receptor for the Th2 cytokine IL-25. In contrast,
IL-1RAcP?/?mice treated with IL-33 exhibit none of these re-
sponses. These results strongly suggest that IL-1RAcP is a member
of the IL-33R complex.
ST2, the ligand binding chain of the IL-33R complex, is ex-
pressed on mast cells and Th2 cells. IL-33 stimulates both of
these cell populations to produce cytokines (Ref. 2 and data not
shown). Interestingly, ST2 is not required for initial Th2 polar-
ization, nor does it appear to be necessary to generate a Th2
immune response, although blockade or absence of ST2 can
attenuate Th2 responses in some disease models (reviewed in
Ref. 9). We tested the influence of IL-1RAcP on Th2 polariza-
tion and cytokine production. CD4?T cells from WT and IL-
1RAcP?/?mice were polarized in Th2 conditions and, after a
brief rest, were stimulated with IL-33 in the presence or absence
of anti-ST2 Ab. Resting Th2 cells from both WT and IL-
1RAcP?/?mice make substantial amounts of IL-5 and IL-13,
but only cells from WT mice respond to IL-33 treatment with
enhanced production of these cytokines. IL-33 effects could be
blocked if WT cells were incubated with anti-ST2 Ab (Fig. 2).
IL-33 had no effect on IL-4 production by either cell genotype
(data not shown). It is interesting to note that Th2 cells respond
to IL-33 in the absence of TCR stimulation. This suggests that
once a Th2 response is initiated, IL-33 can promote Ag-inde-
pendent enhancement of the response.
Although IL-1RAcP is required to mediate the effects of
IL-33 in vivo and on Th2 cells, the possibility exists that this is
due to an indirect rather than a direct interaction of IL-33 and
IL-1RAcP. Therefore, we wished to detect formation of the li-
gand-receptor complex in vitro. In the IL-1R complex, IL-
1RAcP cannot bind IL-1 directly, rather it is hypothesized to
interact with the complex of IL-1 and its primary receptor, IL-
1R1 (4, 7, 10). We were also unable to see a direct interaction
of IL-33 with IL-1RAcP (data not shown). In contrast, the in-
teraction between ST2 and IL-33 can be measured. The affinity
of the IL-33/ST2 interaction was investigated by equilibrium
binding using Biacore with immobilized ST2-Ig fusion protein;
we measured the apparent KDto be 8 ? 2 ? 10?9M (data not
shown). A specific ST2/IL-33/IL-1RAcP complex was mea-
sured by ELISA. We titrated IL-33 or IL-1? into wells con-
taining plate-bound ST2 and soluble his6-tagged IL-1RAcP
(Fig. 3). We detected IL-33R complex formation with an anti-
his6 Ab as the concentration of IL-33, but not IL-1?, increases.
Conversely, if the plates are coated with IL-1R1 instead of ST2,
we detect IL-1R complex formation with increasing amounts of
IL-1? but not IL-33. This result demonstrates that ST2, IL-33,
and IL-1RAcP can form a ligand/receptor complex.
Signal transduction by IL-1RAcP in the IL-1 signaling cas-
cade is mediated by its cytoplasmic TIR domain and involves
recruitment of the adaptor MyD88 and activation of NF-?B
(reviewed in Ref. 1). IL-33 uses the same signaling components
as IL-1, including IL-1R-associated kinase, IL-1R-associated
kinase 4, MyD88, and TNFR-associated factor 6, leading to the
activation of NF-?B and MAPKs (2). MyD88 is required for
IL-33 signaling, as MyD88?/?mice do not respond to IL-33
administration (data not shown). To investigate the contribution
of IL-1RAcP to IL-33 signal transduction, we used a dn form of
IL-1RAcP that contains a stop codon before the TIR domain.
Titration of dn IL-1RAcP into 293FT cells that were transfected
with mouse ST2 and a NF?B-GFP reporter gene construct was
able to decrease the reporter gene signal in response to IL-33.
A similar effect with dnIL-1RAcP was seen when these cells
were stimulated with IL-1? as a positive control (Fig. 4). Thus,
IL-1RAcP is likely to be involved in IL-33-mediated signal
transduction. The different relative levels of GFP?cells mea-
sured after stimulation with IL-1? vs IL-33 may relate to dif-
ferent affinities of the two cytokines for their specific primary
receptor components and/or relate to different primary receptor
numbers for IL-33 and IL-1? expressed on the cell surface
on Th2 cells. Cytokine production after 24 h of stimu-
lation of resting polarized CD4?Th2 cells from WT or
IL-1RAcP?/?in the presence or absence of anti-ST2
Ab. Mean ? SEM of duplicate wells.
IL-1RAcP is required for IL-33 effects
IL-1? or IL-33 was titrated into plates containing soluble his6-tagged mu-
rine IL-1RAcP and plate-bound ST2-Fc (A) or IL-1R1-Fc (B). Peroxidase-
conjugated anti-his6 was used as a detection Ab. Data are representative of
two experiments. Mean ? SEM of duplicate wells.
Detection of the ST2/IL-33/IL-1RAcP complex. Murine
2553The Journal of Immunology
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In the present manuscript, we demonstrate that IL-33 biology is
mediated through a heteromeric receptor complex consisting of
ST2 and IL-1RAcP. Our findings add yet another IL-1-related cy-
tokine to the list of ligands that are functionally dependent on
IL-1RAcP. Receptor promiscuity is a common theme in hemopoi-
etic cytokine biology. IL-1? and IL-1? both use IL-1R1 and IL-
1RAcP, and recently, IL-1F6, IL-1F8, and IL-1F9 were shown to
also use IL-1RAcP (3). In addition to using the same coreceptor,
these IL-1 family members are located in a cluster of genes on
human chromosome 2. In contrast, the IL-1 family member IL-18
is located on a separate chromosome and uses two unique receptor
subunits. Because IL-33 also resides on a separate chromosome
from other IL-1 family members, it was unclear whether its recep-
tors would be shared or unique. ST2 was identified as the primary
ligand-binding receptor in the initial description of IL-33 (2), and
these results show that IL-33, like IL-1 (? and ?), IL-1F6, IL-1F8,
and IL-1F9, uses IL-1RAcP as the second component of its sig-
naling receptor complex.
The shared usage of IL-1RAcP by IL-33 and other IL-1 family
members suggests that these cytokines may have overlapping ac-
tivities. Alternatively, these cytokines could potentially compete
for IL-1RAcP and its associated signaling components. Soluble
ST2 has been shown to attenuate disease severity in collagen-in-
duced arthritis, a model of autoimmune inflammation that is de-
pendent on IL-1 (11, 12). In light of our findings, the mechanism
for this effect may involve the inhibition of IL-1 signaling via the
interaction of soluble ST2 and IL-33 with IL-1RAcP. However,
IL-1RAcP is broadly expressed (13), and may not be a limiting
factor in IL-1 vs IL-33 responses. It is more likely that expression
of the primary ligand-binding chains is the limiting responsive
factor. Indeed, ST2 is a selective marker for Th2 cells, while IL-
1R1 is likely to be expressed on the recently described inflamma-
tory Th17 cell subset (Ref. 14 and K. Bak-Jensen, unpublished
observations). Based on the differential expression of these recep-
tors on T cell subsets, it will be interesting to see whether IL-
1RAcP is involved in effector T cell lineage commitment or
The identification of the complete IL-33 signaling receptor
complex now paves the way for identifying the physiological
role of IL-33. Based on our initial findings and the expression
pattern of ST2, it is likely that IL-33 is involved during the effector
phase of type-2 immune responses involving Th2 cells and/or mast
cells. Interestingly, increased levels of soluble ST2, a likely natural
antagonist of IL-33, have been associated with numerous human
diseases including acute myocardial infarction, asthma with acute
exacerbation, eosinophilic pneumonia, sepsis and trauma, and ex-
acerbated idiopathic pulmonary fibrosis, pointing toward a possi-
ble role for IL-33 in these indications (15–20). Additionally, the
cDNA sequence for what is now known as IL-33 was originally
found as a gene that is highly up-regulated in cerebral arteries after
cranial hemorrhage (21). This, coupled with the fact that IL-33 can
be cleaved in vitro by caspase-1, an apoptotic protease, suggests
IL-33 could be expressed during tissue injury. Further investiga-
tions on the regulation of IL-33 expression, activation, and secre-
tion at the cellular level may provide insight into where and how
IL-33 is expressed during disease.
We thank Melanie Kleinschek, Caroline Diveu, Kyu Hong, Terrill
McClanahan, Dan Gorman, Mehrdad Moshrefi, Sal Santino, and
Sarvesh Adda for technical help and/or helpful discussions.
The authors have no financial conflict of interest.
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Table I. Titration of dn-mIL-1RAcP
Expression Vector (?g)
Percentage of GFP?Cells after
Stimulation with IL-33
Experiment 1 Experiment 2
2554 IL-1RAcP IS A MEMBER OF THE IL-33R COMPLEX
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