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Proc Natl Acad Sci U S A. Jun 16, 2009; 106(24): 9773–9778.
Published online Jun 8, 2009. doi:  10.1073/pnas.0901206106
PMCID: PMC2700978

This article has been retractedRetraction in: Proc Natl Acad Sci U S A. 2012 August 21; 109(34): 13877    See also: PMC Retraction Policy

The cytokine interleukin-33 mediates anaphylactic shock


Anaphylactic shock is characterized by elevated immunoglobulin-E (IgE) antibodies that signal via the high affinity Fcε receptor (FcεRI) to release inflammatory mediators. Here we report that the novel cytokine interleukin-33 (IL-33) potently induces anaphylactic shock in mice and is associated with the symptom in humans. IL-33 is a new member of the IL-1 family and the ligand for the orphan receptor ST2. In humans, the levels of IL-33 are substantially elevated in the blood of atopic patients during anaphylactic shock, and in inflamed skin tissue of atopic dermatitis patients. In murine experimental atopic models, IL-33 induced antigen-independent passive cutaneous and systemic anaphylaxis, in a T cell–independent, mast cell–dependent manner. In vitro, IL-33 directly induced degranulation, strong eicosanoid and cytokine production in IgE-sensitized mast cells. The molecular mechanisms triggering these responses include the activation of phospholipase D1 and sphingosine kinase1 to mediate calcium mobilization, Nuclear factor–κB activation, cytokine and eicosanoid secretion, and degranulation. This report therefore reveals a hitherto unrecognized pathophysiological role of IL-33 and suggests that IL-33 may be a potential therapeutic target for anaphylaxis, a disease of considerable unmet medical need.

Keywords: anaphylaxis, cytokine biology, IL-33

Interleukin (IL)–33 is a new member of the IL-1 family, which includes IL-18 and IL-1β. Like IL-18 and IL-1β, IL-33 was found to have strong immunomodulatory functions (1). However, whereas IL-1β and IL-18 promote proinflammatory and TH1-associated responses, IL-33 induces the production of TH2-associated cytokines and increased levels of serum Ig (1). Moreover, treatment of mice with IL-33 led to high levels of serum IgE and expression of TH2-associated cytokines (1). IL-33 signals via its unique receptor, ST2, and IL-1RAcP (1, 2). ST2, also called T1, DER4 and Fit-2, is highly expressed on mast cells and on TH2 cells (14).

The ST2 gene encodes two isoforms of ST2 proteins: ST2L, a transmembrane form, and the soluble ST2 (sST2), a secreted form that can serve as a decoy receptor of IL-33. We have reported that ST2 is associated with important TH2 effector functions (46). Treatment of mice with either an antagonistic antibody against ST2 or with an ST2-Fc fusion protein led to enhancement of T helper type 1 (TH1) responses and an inhibitory effect on TH2-associated allergic airway inflammation (6). Interestingly, high levels of sST2 has been found in the sera of patients with acute Asthma (7), and serum elevations of sST2 predict mortality and heart failure in patients with acute myocardial infarction (8, 9). Moreover, a role for IL-33/ST2 has also been suggested for arthritis and atherosclerosis (10, 11). However, the role of IL-33/ST2 in systemic anaphylactic shock (SAS or type I hypersensitivity), is unknown.

The symptoms of type I hypersensitivity are largely attributable to the pharmacologically active materials released by activated mast cells (12, 13). The clinical consequences of type I hypersensitivity triggered by mast cells can range from localized reactions including allergic rhinitis, asthma, atopic dermatitis and food allergies, to severe life-threatening systemic reactions such as anaphylaxis. Because mast cells are pivotal to allergic reactions and express a high density of ST2, and because recent reports showed that IL-33 can induce mast cells to produce proinflammatory cytokines in vitro (1417), we investigated the potential role of IL-33 in allergic SAS in humans and in murine models of IgE-mediated passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis (PSA), the most commonly used models to study specific mast cell responses in vivo (1820).

We show here that IL-33 is markedly elevated in the serum of patients during an anaphylactic shock and in atopic human tissue, suggesting a potential role for IL-33 in human pathology. Moreover, we report here that IL-33 plays a pivotal role in experimental anaphylaxis. In the presence of IgE, IL-33 activates mast cell degranulation through molecular mechanisms that trigger key signal transduction events, including phospholipase D1 and sphingosine kinase-1, to mediate calcium mobilization. Thus, our finding suggests a potential therapeutic target against allergy, an important disease with considerable unmet medical need.


IL-33 Expression Is Increased in Patients with Anaphylaxis and Dermatitis.

To investigate a potential role for IL-33 in human atopic allergy, we examined the levels of IL-33 in the serum and tissue from patients during anaphylactic and allergic responses. In atopic patients undergoing surgery, those who developed anaphylactic shock in the operating theater had high levels of IgE and the levels of IL-33 were markedly elevated compared with levels in healthy and atopic control subjects (Figs. 1A, ,11B). Immune-staining and real-time-PCR analysis of samples from the skin lesions show that the level of IL-33 mRNA was substantially higher in the skin lesions of patients with atopic dermatitis compared with noninflamed skin samples (Fig. 1C). The presence of IL-33 was also clearly evident in the skin biopsies of atopic dermatitis but absent in healthy skin (Fig. 1C). These data demonstrate that IL-33 is closely associated with clinical allergic and anaphylactic responses and may play an important role in mediating these diseases. To investigate this hypothesis in greater detail we proceeded with the murine models.

Fig. 1.
IL-33 in atopic patients during anaphylaxis and inflammation. (A) Total IgE levels in healthy donors, atopic controls, and atopic patients with anaphylactic shock. (B) IL-33 levels in healthy donors, atopic controls, and atopic patients with anaphylactic ...

IL-33 Triggers Passive Cutaneous Anaphylaxis.

We first investigated whether IL-33 could contribute to the anaphylactic response in vivo using a murine model of IgE-mediated PCA. One of the key inflammatory events during an allergic reaction is an increase in vascular permeability (18, 19). Mice were sensitized s.c. with anti-DNP IgE antibody and then challenged intravenously 24 hours later with DNP-HSA, IL-33, or IL-33+DNP-HSA, together with Evans blue. Vascular permeability was visualized by the extent of blue staining of the injection sites at the reverse side of skin sections 60 minutes after challenge. Nonsensitized mice showed no vascular permeability (negative control) and mice sensitized with IgE and challenged with DNP-HSA showed the expected level of vascular permeability (positive control). IL-33 was not able to trigger PCA in nonsensitized mice. In contrast, mice sensitized with the IgE and challenged with IL-33 alone showed a comparable level of vascular permeability as mice challenged with DNP-HSA (Fig. 2A). Moreover, IL-33 had an additive effect on the PCA response when injected in conjunction with DNP-HSA (Fig. 2A). Thus, in IgE-sensitized mice, IL-33 can trigger an anaphylactic response and, together with the allergen, IL-33 further enhances anaphylaxis, demonstrating a key role for IL-33 in allergy.

Fig. 2.
Passive cutaneous anaphylaxis (PCA). PCA was induced as described in Materials and Methods. (A–D) Mice were treated as follows: Treatment 1, injected with PBS alone; 2, sensitized with IgE alone; 3, challenged with IL-33 alone; 4, sensitized with ...

To test whether IL-33 could trigger mast cell degranulation in vivo, skin samples at the injection sites were removed and examined histologically. The IL-33–challenged, IgE-sensitized mice displayed the number of mast cells and level of degranulation similar to that of the positive control group (Fig. 2B and [supporting information (SI) Fig. S1]). To confirm that the IL-33/ST2 response in the PCA was mediated by mast cells and not by T-lymphocytes, we performed PCA experiments in RAG1−/− mice, which contain no mature T or B cells (21). IL-33 induced a PCA response and mast cell degranulation in RAG1−/− mice indistinguishable from that in the WT mice (Figs. 2C, ,22D), demonstrating that the IL-33–induced PCA is independent of T or B cells.

To determine the specificity of IL-33–induced PCA, we tested the effect of IL-33 in ST2−/− mice. DNP-HSA induced PCA and mast cell degranulation in both WT and ST2−/− as expected. In contrast, while IL-33 induced PCA and mast cell degranulation in WT mice, IL-33 did not induce an appreciable level of PCA or mast cell degranulation in ST2−/− mice (Figs. 2E, ,22F). Taken together these data demonstrate that IL-33 is capable of triggering mast cell-mediated allergic responses in vivo via ST2 signaling.

IL-33 Triggers Systemic Anaphylaxis.

We then investigated the role of IL-33 in anaphylactic shock, an acute and systemic allergic condition. Mice injected intravenously with anti-DNP IgE antibody and challenged intravenously 16 hours later with IL-33 developed markedly reduced body temperature, reaching 31 °C 30 minutes after IL-33 challenge (Fig. 3A). The rapid decrease in body temperature was completely prevented by the inclusion of anti–IL-33 antibody or soluble ST2 (sST2, a decoy receptor for IL-33) in the IgE inoculums. Furthermore, anti-IL-33 or sST2 injected 5 minutes after the IL-33 challenge still significantly prevented the drop in body temperature. The effect of IL-33 in the induction of anaphylactic shock and the therapeutic influence of anti-IL-33 and sST2 was also reflected in the plasma histamine levels (Fig. 3B), cytokine and chemokine concentrations (Figs. 3C, ,33D), and in immune-cell infiltration into the lungs with concurrent lung inflammation (Fig. 3E, Fig. S2). All these parameters were substantially increased by IL-33 and inhibited by either anti-IL-33 mAb and/or soluble-ST2. Moreover, in IgE sensitized ST2−/− mice, IL-33 failed to induce the anaphylactic response whereas changes in body temperature and increase serum histamine level were observed when the mice were challenged with the DNP-HSA antigen (Fig. 3F). Taken together, these results demonstrate that IL-33 also plays a pivotal role in systemic anaphylaxis.

Fig. 3.
Systemic anaphylactic shock in mice. For systemic anaphylactic shock in wild-type mice, mice were injected i.v. with the various reagents as indicated in the figure and in Materials and Methods (treatments 1–11). (A) Rectal temperature was measured ...

IL-33 Induces Mast Cell Degranulation In Vitro.

IL-33 is able to trigger mast cells to release proinflammatory cytokines in vitro (1417). However, attempts to directly induce mast cell degranulation by IL-33 in vitro had so far not been met with success. Since individuals with allergy or during certain infections exhibit elevated levels of IgE, we therefore stimulated mast cells with IL-33 in the presence of IgE in vitro. Purified mast cells from human and mouse were cultured overnight with IgE and then stimulated with IL-33. Under this culture condition, IL-33 induced the release of β-hexosaminidase (a marker of mast cell degranulation) in a dose-dependent manner (Fig. 4A). In contrast, IL-33 failed to induce mast cell degranulation in vitro in the absence of IgE (Fig. 4B), or if the duration of IgE sensitization was shorter than overnight (data not shown). These results are consistent with our findings above that IL-33 could only induce allergy and anaphylactic shock in IgE-sensitized mice. To test the specificity of IL-33, mast cells were purified from the peritoneal cavity of WT or ST2−/− mice sensitized with anti-DNP-HSA IgE. The cells were then cultured with IL-33 in vitro. IL-33 triggered degranulation in mast cells from WT mice but not in cells from ST2−/− mice (Fig. 4C). Importantly, IL-33 also triggered mast cells to produce eicosanoids, cytokines and chemokines in an ST2-dependent manner (Figs. 4 D–F). Moreover, consistent with our in vivo findings above, IL-33 had additive effects with antigen (DNP-HSA) in the induction of mast cell degranulation of WT mice sensitized with IgE (Fig. 4G). Furthermore, mast cells sensitized with IgE express a substantially higher level of ST2 than nonsensitized mast cells (Fig. 4H), perhaps explaining why IL-33 is capable of inducing mast cell degranulation only after IgE sensitization. These results therefore demonstrate that IL-33 is able to directly trigger degranulation and the synthesis of a wide range of mediators (inflammatory cytokines/chemokines and eicosanoids) via ST2.

Fig. 4.
IL-33 triggers mast cell degranulation and proinflammatory mediators in an ST2-dependent manner. (A) Wild-type mast cells were sensitized with IgE and β-hexosaminidase release was measured after 30 minutes of stimulation with increasing concentration ...

IgE Sensitization of Mice for IL-33–Mediated Anaphylaxis and Mast Cell Degranulation Is Antigen Independent.

To fully characterize the requirement of IgE sensitization for IL-33–mediated anaphylactic responses, we used three additional murine IgE preparations with different antigen specificity from different sources. Mice sensitized with all of the IgE preparations and challenged with IL-33 showed a comparable level of vascular permeability and in vivo mast cell degranulation (Figs. S3A, B). Moreover, mice injected intravenously with all of the IgE antibodies and challenged intravenously 16 hours later with IL-33 developed similar responses, including reduced body temperature, and enhanced levels of serum histamine (Figs. S3C, D). Furthermore, IL-33 also triggered comparable levels of mast cell degranulation in cells sensitized with all of the four IgE preparations in vitro (Fig. S3E).

To investigate whether the IgE-sensitized and IL-33–induced anaphylaxis has physiological relevance, we examined the role of IL-33 in a model of ovalbumin (OVA) sensitization, where endogenous IgE are generated after allergen sensitization. After OVA sensitization, the levels of endogenous IgE were increased to similar levels in wild-type, mast cell-deficient (KitW-sh/W-sh mutant) mice (22), and ST2−/− mice (Fig. 5A). However, when challenged with IL-33, only the wild-type mice, but not the mast cell-deficient or the ST2−/− mice, developed anaphylaxis, as shown by a substantial drop in body temperature (Fig. 5B), increase in blood histamine (Fig. 5C), cytokines, and chemokines (Fig. 5D), and lung inflammation (Fig. 5E). Taken together these data demonstrate that in mice with endogenously generated high levels of IgE, IL-33 induces systemic anaphylaxis in a mast cell and ST2-dependent, but antigen-independent, manner.

Fig. 5.
Effect of IL-33 on ovalbumin (OVA) sensitized mice. (A) OVA induces similar levels of IgE in wild-type (WT), mast cell–deficient (MC−/−) and ST2-null (ST2−/−) mice. (B–E) Mice were treated as follows: treatment ...

Molecular Mechanisms for IL-33 Triggered Mast Cell Degranulation.

We then investigated the molecular mechanism by which IL-33 induces mast cell degranulation, focusing on calcium mobilization and phospholipase activation, the hallmarks of mast cell degranulation. IL-33 triggered a rapid cytosolic calcium response in human mast cells in the absence of IgE (Fig. S4A, nonsensitized). However, in mast cells presensitized with IgE, the calcium response was markedly elevated further (Fig. S4A, IgE-sensitized). Similar results were observed for murine mast cells (data not shown). We have previously shown that at least two different pathways are used by antigen and cytokine receptors to trigger cytosolic calcium signals: the classical pathway that activates phospholipase C to generate IP3 (22, 23), and a novel pathway dependent on the activation of phospholipase D (PLD) and sphingosine kinase (SphK) (2426). IL-33 triggered the activation and translocation of PLD1 (Fig. S4B) and SphK1 in mast cells (Fig. S4C). In contrast, IL-33 did not induce the production of IP3 (Fig. S4D). Using anti-sense knockdown for PLD1 and SphK1 (PLD1 was reduced by 90% and SphK1 by 85%, Fig. S4E), we confirmed that PLD1 and SphK1 were required for IL-33–triggered cytosolic calcium signals (Fig. S4F) and mast cell degranulation (Fig. S4G). It should be noted that for mast cell degranulation, the cells were preincubated overnight with IgE. Using siRNA-knockdown of ST2 in human mast cells (Fig. S4H), we showed that, similar to murine mast cells, the IL-33–mediated human mast cell degranulation is also ST2 dependent. Although ST2 knockdown-cells sensitized to IgE degranulated in response to DNP-HSA, they failed to degranulate in response to IL-33 (Fig. S4I). Therefore, IL-33 induces an ST2-mediated mast cell degranulation by the activation of the novel pathway PLD1 and SphK1, but not the classical phospholipase C/IP3 pathway, leading to calcium mobilization. Similar results were obtained using murine mast cells (data not shown).

IL-33 Triggered Calcium-Dependent Activation of NFκB, Cytokine, Chemokine, and Eicosanoid Synthesis.

It has been suggested that whilst the production of pro-inflammatory cytokines in mast cells is NFκB (p50 and p65) dependent (2729), the induction of Th2 cytokines is NFκB independent (30). We therefore investigated the effect of IL-33 on the activation of NFκB and MAPKs in human mast cells. IL-33 triggered the activation of NFκB (Fig. S5A) and the phosphorylation of ERK1/2 (Fig. S5B) and p38 MAPKs (Fig. S5C). IL-33–stimulated NFκB activity was abrogated in cells pretreated with the intracellular calcium chelator BAPTA-AM (Fig. S5A). This is in agreement with an earlier observation that Ca2+ signal amplitude and frequency play a role in NFκB activation (31). In contrast, the IL-33–induced phosphorylation of MAPKs was not affected by BAPTA (Fig. S4B, C). Consistent with this, BAPTA prevented the generation of IL-1β, IL-3, IL-6, TNF-α, MIP-2, MCP-1, and MIP-1α synthesis, which are dependent on NF-κB activity (27), whereas BAPTA had no effect on IL-33–triggered IL-5, IL-13, Eotaxin-2, RANTES or TARC syntheses, which are independent of the NF-κB pathway (28) (Figs. S5D, E).

Pharmacologically active leukotrienes and prostaglandins are synthesized from arachidonic acid by cytosolic phospholipase A2 (PLA2) and released by the breakdown of membrane phospholipids during mast cell degranulation (32, 33). As IL-33 is able to trigger degranulation and elevate the cytoplasmic Ca2+ necessary for cPLA2 activation, we investigated the role of calcium mobilization in IL-33–induced production of leukotrienes and prostaglandins. IL-33 stimulated human mast cells to produce substantial amounts of PGD2 and LTB4, the production of which were completely abrogated by the presence of BAPTA (Figs. S5F, S5G). Similar results were obtained using murine mast cells (data not shown).

Together, these results demonstrate that IL-33 induces calcium-dependent NFκB activation, cytokine/chemokine, and eicosanoid synthesis during mast cell activation.


Data reported here suggest that IL-33 is elevated in atopic patients only during an allergic-inflammatory response, and that under the experimental conditions, IL-33 induces acute anaphylactic shock (AS), a disorder of considerable importance and unmet medical need. Furthermore, we show that in the presence of IgE, IL-33 induces AS by rapidly activating mast cell degranulation. Our findings therefore have the following important implications: (i) they reveal a hitherto unrecognized pathophysiological role of IL-33; (ii) they provide evidence that IL-33 induce mast cell degranulation; and (iii) IL-33 may be a potential target for treating allergic shock.

Although mast cell activation and degranulation by IL-33 is independent of the presence of T or B cells, the presence of preformed IgE is critical. In vitro the IgE sensitization need to be for at least 16 hours, and shorter sensitization durations failed to primed the mast cells for IL-33–mediated degranulation. This may explain why other studies have failed to show IL-33–triggered degranulation. IL-33 alone is not capable of triggering AS. This requirement of IgE may represent a failsafe control mechanism such that the expression of IL-33 alone, induced by unrelated infection or immunological activation, would not automatically lead to anaphylactic shock or acute allergic response. Conversely, IL-33 can act in an additive fashion with antigen-mediated reaction, to further enhance AS. Thus IL-33 appears to play a critical but controlled role in allergic shock response.

IgE sensitization substantially increased mast cells ST2 expression (Fig. 4H). This was also recently reported by Ho et al. (15). Moreover, the amplitude and duration of the calcium response triggered by IL-33 in IgE-sensitized mast cells was also markedly increased compared to the non-sensitized cells. It is thus likely that IgE receptor occupancy increases ST2 density on mast cells such that IL-33 would then achieve sufficient signaling strength (as shown for the calcium response, Fig. S1A) to induce mast cell degranulation.

Of particular interest is the finding that in human atopic patients IL-33 is substantially elevated during systemic shock and localized allergic reaction, but not in patients without inflammation. Importantly, the systemic anaphylactic shock in mice could be prophylactically and therapeutically attenuated by sST2 (a decoy receptor of IL-33), or by anti–IL-33 antibody. Therefore, our data suggest that endogenous IL-33 may contribute to the pathology of IgE-associated diseases, the importance of which warrants further investigation.

It is well established that mast cells are key effector cells in triggering the immediate Type-I hypersensitivity in allergic patients. Mast cells are predominantly present in the skin, airways, and gastrointestinal tract. Allergen-bound IgE triggers an array of signaling pathways, which lead to degranulation and the release of histamine, proteases, cytokines, as well as de novo synthesis of the arachidonic acid metabolites, such as leukotrienes and prostaglandins. These mast cell-generated proinflammatory mediators then cause the immediate symptoms of allergic diseases, such as rhinitis, conjunctivitis and asthma. Despite extensive efforts, the etiology and pathogenesis of most allergic diseases remain poorly understood, and effective therapies with limited side effects are lacking. The key factor that may tip the balance between the physiological and the pathophysiological manifestation of mast cells has long been elusive. Data presented here may go some way to resolve this conundrum. We demonstrate here that, in IgE-sensitized mast cells, IL-33 may be that key factor tipping mast cell activation and degranulation and thus may represent a potential target for treatment of AS.

At this stage it is not known whether the clinical systemic shock and localized allergic reaction stimulated IL-33 production or that IL-33 triggered these clinical symptoms. What is clear, however, is that atopy alone is not sufficient to trigger anaphylaxis. Based on our animal studies, it may be that under conditions where an atopic patient secretes high levels of IL-33 because of a strong inflammatory condition, this IL-33 might then trigger the mast cell responses even in the absence of an IgE-specific allergen. We also showed that IL-33 levels are elevated in atopic dermatitis only in inflamed tissue. This would suggest that during allergic inflammation IL-33 is up-regulated. We screened for patients who were atopic and developed anaphylactic shock in the operating theatre. IL-33 may indeed be elevated in other systemic inflammatory conditions, such as peanut or drug-mediated anaphylactic shock. This is currently being addressed.

Materials and Methods

Clinical Serum Samples and Skin Biopsy Samples.

Male and female patients aged >18 years with atopic dermatitis (AD) were enrolled in the study. For full description, see SI Materials and Methods.

Induction and Measurement of PCA and AS.

Experiments were performed on 8–10-week-old mice. For full details of the procedures, see SI Materials and Methods.

In Vitro Assays.

Human mast cells were derived from CD34+ hematopoietic progenitor cells isolated from umbilical cord blood and cultured as previously described (26, 34). Murine mast cells were isolated from the peritoneal cavity and cultured as previously described (35). For full description on in vitro assays, see SI Materials and Methods.

Statistical Analysis.

Statistical differences between control and treatment groups were calculated using unpaired Student's t test. P < 0.05 was considered statistically significant.

Supplementary Material

Supporting Information:


We thank M. Rauff (National University Hospital, Singapore) for help in procuring human samples. We thank A.-K. Fraser-Andrews and H. Arthur for proofreading the manuscript. This work was supported by grants from The Wellcome Trust and The Medical Research Council, U.K.


The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0901206106/DCSupplemental.


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