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Proc Natl Acad Sci U S A. 2010 Oct 26; 107(43): 18581–18586.
Published online 2010 Oct 11. doi:  10.1073/pnas.1003059107
PMCID: PMC2972966

IL-33 is a crucial amplifier of innate rather than acquired immunity


IL-33, a member of the IL-1-related cytokines, is considered to be a proallergic cytokine that is especially involved in Th2-type immune responses. Moreover, like IL-1α, IL-33 has been suggested to act as an “alarmin” that amplifies immune responses during tissue injury. In contrast to IL-1, however, the precise roles of IL-33 in those settings are poorly understood. Using IL-1- and IL-33-deficient mice, we found that IL-1, but not IL-33, played a substantial role in induction of T cell-mediated type IV hypersensitivity such as contact and delayed-type hypersensitivity and autoimmune diseases such as experimental autoimmune encephalomyelitis. Most notably, however, IL-33 was important for innate-type mucosal immunity in the lungs and gut. That is, IL-33 was essential for manifestation of T cell-independent protease allergen-induced airway inflammation as well as OVA-induced allergic topical airway inflammation, without affecting acquisition of antigen-specific memory T cells. IL-33 was significantly involved in the development of dextran-induced colitis accompanied by T cell-independent epithelial cell damage, but not in streptozocin-induced diabetes or Con A-induced hepatitis characterized by T cell-mediated apoptotic tissue destruction. In addition, IL-33-deficient mice showed a substantially diminished LPS-induced systemic inflammatory response. These observations indicate that IL-33 is a crucial amplifier of mucosal and systemic innate, rather than acquired, immune responses.

Keywords: asthma, colitis, cytokine, interleukin-33, sepsis

IL-33, which is a member of the IL-1 family of cytokines that includes IL-1 and IL-18, induces Th2-type immune responses such eosinophil-rich inflammation in the intestines and lungs associated with elevated numbers of blood eosinophils and increases in serum concentrations of IgE, IgA, IL-5, and IL-13 in mice, dependent on IL-13 (1). IL-33 is important for Th2 cytokine-associated host defense against nematode infection through signals from IL-33 receptor (IL-33R), which consists of ST2 (also called T1, DER-4, Fit-1, or IL-1RL1) and IL-1R accessory protein (IL-1RAcP) (2, 3). As a Th2-inducing cytokine, IL-33 is considered to be involved in the development of allergic diseases such as atopic asthma (2, 3). IL-33 is also known to ameliorate the development of Th1 cytokine-associated atherosclerosis in apolipoprotein E-deficient mice (4) and accelerate Th17 cell-mediated murine arthritis (5). Thus, it is now thought that IL-33 acts not only as a Th2-inducing cytokine, but also as a proinflammatory cytokine, like IL-1 and IL-18, in various immune responses. Using ST2-deficient (ST2−/−) mice and mice treated with anti-ST2 Ab or soluble ST2-Fc-fusion proteins, however, it was reported that the roles of ST2 were not identical in certain immune responses such as allergic airway inflammation (68) and LPS-induced endotoxin shock (9, 10). Therefore, we generated IL-33−/− mice to comprehensively examine the roles of IL-33 in the following disease models: allergic airway inflammation; LPS-induced endotoxin shock, contact, and delayed-type hypersensitivity; experimental autoimmune encephalomyelitis; Con A-induced hepatitis; streptozocin-induced diabetes; and T cell-independent dextran sodium sulfate-induced colitis.

Results and Discussion

IL-33 in Allergic Airway Inflammation.

Allergic airway inflammation induced by OVA is a well-established mouse model of human asthma. IgE, mast cells, and IL-1 are responsible for the development of airway inflammation in mice sensitized with OVA in the absence of alum (IgE-dependent protocol), but they are not essential for that event in the presence of alum (IgE-independent protocol) (11). At present, the role of IL-33/ST2 in allergic airway inflammation using ST2−/− mice remains controversial (68). That is, OVA-induced airway inflammation developed normally in ST2−/− mice that had been sensitized twice with OVA emulsified in alum (68), whereas it was attenuated in ST2−/− mice that had been sensitized once with OVA emulsified in alum (8) and exacerbated in wild-type or Rag-1−/− mice that had undergone adoptive transfer of ST2−/− DO11.10 Th2 cells (7).

During airway inflammation induced by two sensitizations with OVA emulsified in alum, IL-33−/− mice, which were newly generated (Fig. S1), showed attenuated eosinophil influx into the bronchoalveolar lavage (BAL) fluid, airway hyperresponsiveness, and pulmonary inflammation (Fig. 1 A-C). The number of lymphocytes in BAL fluids was also reduced in IL-33−/− mice compared with IL-33+/+ mice, although their proportions of CD3+CD4+ST2+ cells were comparable (IL-33+/+: 2.2 ± 0.5%, n = 9 and IL-33−/−: 2.0 ± 0.4%, n = 9) after the last OVA challenge. In contrast, the IL-4 and IL-5 levels in the BAL fluid and serum OVA-specific IgE production were only slightly (i.e., not significantly) reduced in IL-33−/− mice after the last OVA challenge (Fig. S2 A and B). Interestingly, IL-33 deficiency showed no effect on OVA-specific spleen cell proliferation or cytokine secretion (Fig. S2C).

Fig. 1.
IL-33 is required for development of an IgE/mast cell-independent OVA-induced allergic airway hypersensitivity response. Mice were sensitized twice with OVA emulsified in alum on days 0 and 14. The mice were challenged intranasally with OVA or saline ...

We also found that IL-33 deficiency significantly diminished inflammatory cell influx into the BAL fluid during airway inflammation induced by an extract derived from house dust mites (HDM) (Fig. 2A). HDM is a major source of allergens in allergic patients and can provoke allergic airway inflammation resembling human asthma in mice by facilitating barrier disruption, inflammation, and allergen sensitization of the airways through TLR4-dependent innate and acquired immunity (1214).

Fig. 2.
IL-33 is essential for the development of innate-type airway inflammation. The number of cells in BAL fluids during airway inflammation induced by HDM in IL-33+/+ and IL-33−/− mice (A) and induced by papain in C57BL/6-wild-type and Rag-2 ...

These findings suggest that IL-33 is important for inducing antigen-dependent Th2-associated local airway inflammation but is mostly dispensable for antigen-specific Th2 cell differentiation. Indeed, IL-33 can directly enhance eosinophil activation in vitro (15) and induces airway inflammation without Th2 cell activation dependent on IL-13 (16). In support of this notion, IL-33 induced airway eosinophilia even in T/B cell-deficient Rag-2−/− mice (Fig. S3), indicating that acquired immune cells are not essential for the setting. Likewise, we found that inhalation of a protease allergen, papain, which is regarded as a cause of occupational asthma (17), induced strong airway eosinophilia in naïve Rag-2−/− mice and naïve wild-type mice (i.e., without prior immunization with papain) (Fig. 2B), although papain-induced airway inflammation has been considered to be mediated by Th2 cells when mice were first sensitized with papain (18).

Although IL-33 proteins were constitutively expressed in the lungs of naïve mice (Fig. S1C), papain inhalation resulted in increased IL-33 mRNA expression in the lungs of wild-type mice but not Rag-2−/− mice (Fig. S4A). The increased papain-induced inflammation seen in Rag-2−/− mice may be caused by the lack of Treg cells, as described (19). T/B cell-independent papain-induced innate-type airway inflammation developed in both C57BL/6 and BALB/c mouse strains, although the BALB/c strain was less sensitive to both papain and IL-33 than the C57BL/6 strain (Fig. S4 C and D). Interestingly, papain-induced airway eosinophilia was profoundly impaired in IL-33−/− mice and IL-4−/−IL-13−/− mice (Fig. 2C), suggesting that IL-4 and/or IL-13 derived from IL-33-stimulated innate cells (i.e., Siglec-F+ cells, but not Gr1+, c-Kit+, FcεRIα+, DX5+, or CD11c+ cells; Fig. S5), but not T cell-derived IL-4 and/or IL-13, is important for the event. These findings indicate that IL-33 is crucial for induction of innate-type allergic airway inflammation, whereas it is mostly indispensable for papain-induced airway eosinophilia.

IL-33 in Type IV Hypersensitivity.

Type IV hypersensitivity responses such as contact hypersensitivity (CHS) developed normally in TLR4−/− mice (20) but were abolished in Rag-2−/− mice (Fig. S6A), indicating that acquired, rather than innate, immune cells are an important effector for the induction of CHS. Moreover, it is thought that Th2 cytokines are involved in the pathogenesis of CHS (11), suggesting a contribution of IL-33 to the induction of CHS. After FITC and 2,4-dinitrofluorobenzene challenge, ear swelling was also normally induced in IL-33−/− mice but attenuated in IL-1α/β−/− mice (Fig. S6 B and C). IL-33−/− mice also showed normal responses in terms of the levels of skin DC migration and FITC-specific proliferation, IL-4 production by LN cells after FITC sensitization, the degree of skin inflammation, myeloperoxidase (MPO) activity, eosinophil peroxidase (EPO) activity, and serum FITC-specific IgG1 and IgG2a levels after FITC challenge (Fig. S7 AE).

Moreover, methylated BSA (mBSA)-induced delayed-type hypersensitivity (DTH), which is another type IV hypersensitivity that is mediated by Th17 cells (21) and suppressed by Th1 cells (22), was also normally induced in IL-33−/− mice but impaired in IL-1α/β−/− mice (Fig. S8A). IL-33−/− mice also showed normal levels of Ag-specific T cell responses, a normal Th17/Treg proportion after Ag sensitization and normal serum levels of mBSA-specific IgG1 and IgG2a after Ag challenge (Fig. S8 BD). Therefore, IL-33 seems to be unnecessary for the development of these T cell-dependent acquired immune responses.

IL-33 in Autoimmunity.

ST2 was shown to contribute to the development of a Th17 cell-mediated autoimmune disease, collagen-induced arthritis (5). However, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), which is another Th17 cell-mediated autoimmune disease, developed normally in IL-33−/− mice but was attenuated in IL-1α/β−/− mice (Fig. S9A). The levels of MOG-specific LN cell proliferation and IL-17 and IFN-γ production, the proportions of Th17 and Treg cells among LN cells after MOG sensitization, and the levels of MOG-specific IgG1 and IgG2a in sera after MOG challenge were comparable between IL-33−/− and IL-33+/+ mice (Fig. S9 BD). These observations indicate that IL-33 is not essential for the pathogenesis of this Th17 cell-mediated EAE.

IL-33 in Tissue Injury.

Like pro-IL-1α, pro-IL-33, but not caspase-cleaved IL-33 (2325), has biological activity and is suggested to act as an alarmin, an endogenous danger signal that alerts immune cells, in necrosis-, rather than apoptosis-, associated tissue injury during trauma and/or infection (23, 24). Streptozocin-induced diabetes and Con A-induced hepatitis are well-established models of apoptotic tissue injury via TRAIL and Fas on T cells and/or NKT cells (26, 27). Hyperglycemia during streptozocin-induced diabetes and the serum levels of GOT and GPT activities during Con A-induced hepatitis were comparable between IL-33+/+ and IL-33−/− mice (Fig. S10), again indicating that IL-33 is not essential for the development of T/NKT cell-mediated tissue injury during these acquired immune responses.

Development of dextran sodium sulfate (DSS)-induced colitis is known to be triggered by enterobacteria via TLR (28), independently of T cells, NK cells, NKT cells, and mast cells (2931). We found that IL-33−/− mice showed higher viability than IL-33+/+ mice until approximately day 12 during 3.5% and 3.0% DSS-induced colitis, whereas the final viability on days 14 and 15 was nearly the same (Fig. 3). After treatment with 3.0% DSS, body weight loss, inflammation, and decreased MPO activity in the colon were significantly more pronounced in IL-33−/− mice compared with IL-33+/+ mice until day 8 (Fig. 4 AC). These observations suggest that IL-33 is important for induction of local inflammation at the onset of DSS-induced colitis. However, body weight recovery was markedly delayed in IL-33−/− mice compared with IL-33+/+ mice after changing from drinking water containing 3.0% DSS to plain drinking water (Fig. 3). On day 15, the lesion was almost recovered but was still observed in a small proportion of the colons of both IL-33+/+ and IL-33−/− mice (Fig. 4A), and the severity of tissue damage in the colon lesions was similar in IL-33+/+ and IL-33−/− mice (Fig. 4B). On day 15, the MPO activity in the homogenates of whole colons from both strains returned to the level seen in naïve mice (Fig. 4C). The levels of IL-33 and proinflammatory mediators (i.e., IL-1β, TNF, KC, and MIP-2) that are involved in neutrophilia were similarly increased in the colon of both IL-33+/+ and IL-33−/− mice compared with naïve mice on day 8 after DSS treatment (Fig. S11). The expression levels of IL-1β, KC, and MIP-2 in the colon of IL-33+/+ mice on day 15 were higher than on day 8 (Fig. S11A), whereas the expression levels of IL-33 and TNF were reduced on day 15 (Fig. S11). In the setting, KC and MIP-2 expression was significantly decreased in the colon of IL-33−/− mice on day 15 after DSS treatment (Fig. S11). Normal expression of potent proinflammatory cytokines such as TNF and IL-1β may induce significant inflammation in IL-33−/− mice during DSS-induced colitis. However, these observations suggest that IL-33 deficiency leads to delayed local inflammation by reducing neutrophil-chemoattractant factors, resulting in delayed resolution of tissue damage during DSS-induced “innate” colitis.

Fig. 3.
IL-33 is crucial for T/NKT cell-independent DSS-induced colitis. Mice were provided sterile water containing 3.5% or 3.0% DSS ad libitum for 7 d, followed by 14–15 d of regular drinking water. The change in body weight and survival during 3.5% ...
Fig. 4.
IL-33 is involved in the induction of inflammation during DSS-induced colitis. Colon sections (A) (hematoxylin-eosin, 100×. Representative data from three to five mice are shown), score of the severity of colitis (B) (only inflamed sites were ...

IL-33 in Endotoxin Shock.

The LPS-induced systemic inflammatory response is characterized by dysfunction of multiple organs, including the liver and lung. LPS-stimulated macrophages release IL-33 (32), and IL-33 enhances IL-6 (Fig. S12A) and TNF production (33) by LPS-stimulated macrophages, suggesting involvement of IL-33 in the setting. Indeed, IL-33−/− mice were resistant to endotoxin shock in comparison with IL-33+/+ mice after LPS injection (Fig. 5A). We also found that production of IL-6, IL-1α, and IL-1β, but not TNF, by thioglycolate-induced peritoneal macrophages of IL-33−/− mice was reduced compared with IL-33+/+ mice at 9 and/or 48 h after LPS stimulation (Fig. 5B). LPS-mediated IL-6 and TNF production by macrophages is known to be differentially regulated by nuclear IκB proteins such as IκBNS (34) and IκBζ (35), which was originally identified as an IL-1-, but not TNF-, inducible nuclear protein (36, 37). Therefore, like IL-1, IL-33 may be involved in host defense against bacteria and in innate inflammatory responses triggered by bacteria by inducing production of IL-6 and IL-1, rather than TNF, by LPS-stimulated macrophages via distinct nuclear protein activation.

Fig. 5.
IL-33 is important for LPS-induced endotoxin shock. (A) Mice were injected intraperitoneally with LPS (5–20 mg/kg; n = 10–13), and survival was monitored. (B) Thioglycolate-induced peritoneal macrophages were stimulated with LPS for 9 ...

Unlike endotoxin shock induced by a single LPS injection (Fig. 5A), the susceptibility to a lethal dose of LPS was comparable in IL-33+/+ and IL-33−/− mice that had been injected once with a low dose of LPS (Fig. S12C) or had been made tolerant to LPS by repeated injection of a low dose of LPS (Fig. S12D). These observations suggest that IL-33 is important for acute responses, rather than secondary responses and tolerance, to LPS.

However, as in the case of OVA-induced airway inflammation (68), the contribution of ST2 to that response is controversial. Production of each of IL-6, IL-12, and TNF by LPS-stimulated macrophages was suppressed by blockade of ST2 signals using soluble ST2-Fc fusion proteins, and BALB/c mice treated with soluble ST2-Fc fusion proteins were resistant to LPS-induced endotoxemia (9). Conversely, production of these cytokines by LPS-stimulated BALB/c-ST2−/− macrophages was increased, and BALB/c-ST2−/− mice were highly susceptible to LPS-induced endotoxemia (10). On the other hand, it was reported that LPS-induced TNF production was normal in BALB/c-ST2−/− macrophages (33). Thus, in contrast to treatment with soluble ST2-Fc fusion proteins, ST2 deficiency may result in increased formation of IL-1R (IL-1R1 and IL-1RAcP) due to failed formation of IL-33R (ST2 and IL-1RAcP), causing cytokine hyperproduction by ST2−/− macrophages in response to IL-1. Notably, ST2−/− macrophages produced larger amounts of cytokines than wild-type macrophages after IL-1α or IL-1β treatment (10). Although IL-1R1−/− mice showed normal susceptibility to LPS-induced endotoxin shock (38), IL-1R antagonist-deficient mice, which have excessive IL-1-signaling, showed heightened susceptibility (39). Thus, IL-1 is not required for induction of LPS-induced endotoxin shock, but excessive IL-1 production leads to amplified susceptibility to LPS, as seen in ST2−/− mice. Distinct phenotypes were also seen in IL-18−/− and IL-18Rα−/− mice: EAE developed normally in IL-18−/− mice but was dramatically reduced in IL-18Rα−/− mice (40), suggesting a contribution by a ligand(s) other than IL-18, i.e., IL-1F7 (41), in the setting. As is well known, the function of the IL-1 family of cytokines is elaborately controlled by functional/decoy receptors and antagonists (41). Therefore, like IL-18R, ST2 may be a component of receptors for other ligand(s) besides IL-33. Alternatively, IL-33 may bind to other functional receptors besides ST2. Accordingly, for elucidation of the precise roles of IL-33 in immune responses, studies using IL-33−/−, rather than ST2−/−, mice have been highly anticipated.

Taken all together, IL-33 seems to play a critical role in various types of innate-type inflammation in the lung and gut, whereas it is dispensable for acquired immune responses. Of note, IL-33 is indispensable for innate airway inflammation induced by papain. We were also able to show that IL-33 is crucial as an alarmin for innate-type, but not acquired-type, tissue injury-related inflammatory responses such as LPS-induced endotoxin shock.


LPS-Induced Sepsis.

LPS (Escherichia coli serotype 0111:B4; Sigma-Aldrich)-induced sepsis was evaluated as described (38).

DSS-Induced Colitis.

Mice were provided sterile water containing 3.0% or 3.5% DSS (reagent grade, MW = 36,000–50,000; MP Biomedicals) ad libitum for 7 d, followed by 14 d of plain drinking water.

Other Methods.

The details are provided in SI Methods.

Supplementary Material

Supporting Information:


We thank Drs. Yoichiro Iwakura (The Institute of Medical Science, University of Tokyo) and Andrew McKenzie (Medical Research Council, Cambridge, United Kingdom) for providing IL-1α/β−/− mice and IL-4−/−IL-13−/− mice and Shuhei Fukuda, Hiromi Wakita, Michiko Yamada, and Noriko Hashimoto for their excellent technical assistance. This work was supported by a National Institute of Biomedical Innovation Grant (to H.S.), a Research on Allergic Disease and Immunology in Health Labor Sciences Research Grant (to H.S.), and grants from the MEXT, Japan [Grant-in-Aid for Scientific Research (B) (to H.S.), Grant-in-Aid for Young Scientists (B) (to K. Oboki and S.N.], and the Program for Improvement of Research Environment for Young Researchers, The Special Coordination Funds for Promoting Science and Technology (to S.N.).


The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1003059107/-/DCSupplemental.


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