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Role of Interleukin-33 in Innate-Type Immune Cells in Allergy


Susumu Nakae, Hideaki Morita, Tatsukuni Ohno, Ken Arae, Kenji Matsumoto and Hirohisa Saito [About this authors]


Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is preferentially and constitutively expressed in epithelial cells, and it is especially localized in the cells' nucleus. The nuclear IL-33 is released by necrotic cells after tissue injury and/or trauma, and subsequently provokes local inflammation as an alarmin, like high-mobility group box protein-1 (HMGB-1) and IL-1α. IL-33 mainly activates Th2 cells and such innate-type immune cells as mast cells, basophils, eosinophils and natural helper cells that express IL-33R (a heterodimer of IL-1 receptor-like 1 [IL-1RL1; also called ST2, T1, Der4, fit-1] and IL-1 receptor accessory protein [IL-1RAcP]). That activation causes the cells to produce Th2 cytokines, which contribute to host defense against nematodes. On the other hand, excessive and/or inappropriate production of IL-33 is also considered to be involved in the development of such disorders as allergy. In this review, we summarize current knowledge regarding the pathogenic roles of IL-33 in the development of allergic inflammation by focusing on its effects on innate-type immune cells.

allergy, basophil, interleukin-33, mast cell, natural helper cell

Received: 14 January 2013.

Allergology International 2013; 62: 13-20


IL-33, a ligand for IL-1RL1 (also called ST2, T1, Der4 and fit-1), which is a member of the Toll/IL-1 receptor superfamily,1 is produced/expressed by various types of immune cells such as mast cells, macrophages and dendritic cells (DCs), and non-immune cells such as endothelial, epithelial and smooth muscle cells and fibroblasts2 (Fig. 1). IL-33 is also known to be identical to DVS27, a gene transcript that is upregulated in vasospastic cerebral arteries after subarachnoid hemorrhage,3 and nuclear factor from high endothelial venules (NF-HEV), a transcript expressed in the nucleus of endothelial cells.4 IL-33 is localized in the nucleus—due to its association with heterochromatin via a helix-turn-helix motif within the N-terminal part—where it acts as a transcriptional repressor, at least in vitro.5, 6 Thus, like IL-1α and high-mobility group box 1 (HMGB1),7, 8 IL-33 is considered to act not only as a proinflammatory cytokine but also a nuclear factor. However, the pathophysiological roles of IL-33 as a nuclear factor remain unclear.

IL-1β and IL-18, members of the IL-1 family of cytokines, are initially synthesized as precursor forms—which lack the amino acid sequences of signal peptides—in the cytosol and fail to induce cell activation.9, 10 After exposure to certain stimuli in cells, the IL-1β and IL-18 precursors are proteolytically cleaved by caspase-1 through activation of inflammasomes, after which the cleaved forms become biologically active and are secreted.9, 10 In an early study, IL-33 was similarly considered to be biologically activated by cleavage by caspase-1 and then secreted via an unconventional secretion mechanism.1 Unlike IL-1β and IL-18, however, full-length IL-33—which does not have a typical caspase-1 cleavage site such as seen in IL-1β and IL-18—is bioactive even without caspase-1-dependent cleavage11-13 Thus, the caspase-mediated proteolytic cleavage during apoptosis associated with activation of inflammasomes is not necessary for activation and secretion/release of IL-33. Conversely, IL-33 released by necrotic cells without cleavage by caspases or calpain, which is required for IL-1α, has biological activity.13, 14 In addition, in contrast to cleaved-form IL-33 generated by caspase, cleaved-form IL-33 generated by neutrophil elastase and cathepsin G from full-length IL-33 released by cells during tissue injury has -10 fold higher biological activity than full-length IL-33.15 Thus, like HMGB-1 and IL-1α, IL-33 is considered to be an alarmin or a damage-associated molecular pattern (DAMP) molecule that is released by necrotic cells after tissue injury and/or trauma.


IL-33R is a heterodimer comprised of IL-1RL1 and IL-1 receptor accessory protein (IL-1RAcP).16-18 It is expressed on various types of cells and induces activation of those cells by activation of transcription factors such as NF-κB and AP-1 via a signal pathway [consisting of recruitment of myeloid differentiation factor 88 (MyD88) to the Toll/IL-1R domain in the cytoplasmic region of IL-1RL1, IL-1R-associated kinase (IRAK), TNF receptor-associated factor 6 (TRAF6) and/or mitogen-activated protein kinase (MAPK)] after binding of IL-33, in a similar manner with other IL-1R family members such as IL-1R and IL-18R1, 19 (Fig. 2).

Regarding IL-1RL1, two major forms, i.e., transmembrane- and soluble-forms, are produced from the IL-1RL1 gene as a result of alternative splicing under the control of two distinct promoters.2, 20, 21 The transmembrane-form IL-1RL1 is considered to be a functional component of IL-33R, whereas soluble-form IL-1RL1 is regarded as a decoy receptor for IL-33, like soluble IL-1R for IL-1α and IL-1β.2, 20, 21


Human peripheral blood or cord blood progenitor cell-derived mast cells (MCs) and mouse peritoneal and bone marrow-derived cultured MCs constitutively express IL-1RL116, 18, 22-25 and produce various cytokines and chemokines (i.e., IL-1β, IL-6, IL-13, TNF, GM-CSF, CXCL8, CCL1 and CCL2) that induce expression of mouse mast cell protease-6, prolong survival and promote adhesion of naïve human and murine MCs without inducing degranulation in response to IL-3322-24, 26, 27 (Fig. 2). IL-33 can enhance IgE/Ag-, monomeric IgE-, C5a-, stem cell factor (SCF)- and nerve growth factor (NGF)-mediated cytokine production in human and mouse MCs, and a human mast cell line, HMC-1.2, 21, 28 On the other hand, long-term exposure of human and mouse MCs to IL-33 resulted in attenuation of IgE/Ag-FcεRI-mediated degranulation due to down-regulation of PLCγ1 and Hck expression, although short term exposure to IL-33 did not influence that degranulation directly.29


IL-33 can induce production of such cytokines and chemokines as IL-4, IL-5, IL-6, IL-8, IL-13, GM-CSF, CCL2, CCL3 and CCL4 and cell adhesion by promoting CD11b expression—without inducing degranulation or migration—in human and/or mouse naïve basophils that constitutively express IL-1RL1.30-33 IL-33 enhances IgE-mediated degranulation and migration as well as IgE- and IL-3-mediated cytokine and chemokine production in human and mouse basophils28, 30-32, 34 (Fig. 2). IL-33 also enhances the receptor for leptin—which is an adipokine and a member of the IL-6 family of cytokines—on human basophils, suggesting that IL-33 may be involved in metabolic abnormalities associated with inflammation via basophil activation.35


Human eosinophils also express IL-1RL1,36, 37 and IL-33 enhances eosinophils' survival, cell adhesion accompanied by increased expression of CD11b and ICAM-1, and production of such cytokines and chemokines as IL-6, IL-8, IL-9 and CCL2, as well as superoxide31, 36-38 (Fig. 1). The role of IL-33 in degranulation of human eosinophils is controversial. IL-33 failed to induce degranulation as assessed by release of eosinophil-derived neurotoxin (EDN) and leukotriene C4,36 but others conversely found it to induce degranulation as assessed by EDN release.37 In humans, IL-33-stimulated basophils enhanced IL-17 production by CCR6+ CD4+ T cells and by effector and central memory T cells, suggesting basophil involvement in development of Th17-mediated inflammatory disorders such as inflammatory bowel disease.39


Recently, a number of IL-5- and IL-13-producing Lin- c-kit+ Sca-1-/+ innate lymphoid cells, such as natural helper (NH) cells, multi-potent progenitor type 2 cells (MPPtype2 cells), nuocytes and innate helper type 2 (Ih2) cells, were identified as populations that are distinct from lymphoid progenitors, lymphoid tissue inducer cells and RORγt+ ILCs.40-46 Also, GATA-3 was found to be a key transcription factor for development of those cells47 (Table 1). Lin- c-kit+ Sca-1+ NH cells, found in fat-associated lymphoid clusters in visceral adipose tissue, constitutively express IL-1RL1 and produce larger amounts of IL-5, IL-6 and IL-13, but not IL-4, than basophils and mast cells in response to IL-33 alone or IL-2 + IL-25, but not IL-25 alone. They are involved in host defense against helminths such as Nippostrongylus brasiliensis (N. brasiliensis) via IL-5- and IL-13-dependent eosinophilia and goblet cell hyperplasia.40, 48 IL-1RL1-expressing Lin- c-kit+ Sca-1+ nuocytes and IL-1RL1-expressing Lin- c-kit+ Sca-1- Ih2 cells accumulate in the mesenteric lymph nodes, spleen and liver of mice injected with IL-25 or IL-33 and infected with N. brasiliensis. Both nuocytes and Ih2 cells as well as NH cells are known to be crucial for host defense against N. brasiliensis41, 43, 49 and the development of allergic airway inflammation.50, 51 Expansion of Lin- c-kit+ Sca-1+ MPPtype2 cells, which do not express IL-1RL1, is observed in mesenteric lymph nodes and gut-associated lymphoid tissues, including Peyer's patches, of mice injected with IL-25 or infected with helminths such as N. brasiliensis and Trichuris muris, contributing to host defense against such pathogens.42 Although IL-33 and/or IL-25 are key cytokines for expansion of IL-5- and IL-13-producing ILCs such as NH cells, nuocytes, Ih2 cells and MPPtype2 cells in mice, except for NH cells it is unclear whether these cells produce IL-5 and/or IL-13 in response to IL-33 or IL-25.

Brickshawana et al. reported that IL-33-responsive c-Kit-negative Sca-1+ CD25+ cells differed from c-Kit-positive NH cells, nuocytes and Ih2 cells.52 Monticelli et al. identified Lin- c-Kit+ Sca-1+ CD90+ CD25+ CD127 (IL-7Rα)+ IL-1RL1+ cells, which produce IL-5 and IL-13 in response to IL-33, among resident cells in human and mouse lungs, and found that differentiation of those cells requires expression of a transcription factor, Id2.53 Ikutani et al. found two types of c-Kit+ ILCs, which produce IL-5 alone or IL-13 alone in response to IL-33 or IL-25, in the peritoneal cavity, lung and gut of mice.54 Bartemes et al. also found Lin- c-Kit+ Sca-1+ CD25+ ILCs that produced IL-5 and IL-13 in response to IL-33 in the murine lung.55 However, unlike Ikutani et al., these cells did not respond to IL-25.55


Genetic polymorphism of IL-33 and IL-1RL1 is suspected of causing susceptibility to development of asthma in certain patients.56 In support of that, increased expression/production of IL-33 and/or IL-1RL1 was shown in specimens from asthma patients.57-60 Treatment of mice with IL-33 resulted in development of eosinophil-associated inflammation in the lung and gut dependent on IL-13, but independently of B cells (that is, IgE), T cells and NKT cells.1, 61 However, airway eosinophilia after IL-33 inhalation was observed even in mast cell-deficient mice and mice whose NK-cell and basophil populations were depleted61 by injection of anti-asialo GM1 mAb.62 These observations suggest that mast cells and basophils are not essential for IgE-independent IL-33-mediated airway eosinophilia. Rather than mast cells and basophils, lung NH cells are suggested to be involved in development of IL-33-mediated airway eosinophilia. A plant-derived cysteine protease, papain, which is homologous to Der P1 and Der f1 from house dust mites and human cathepsin B,63 induces airway inflammation by disrupting tight junctions between epithelial cells in mice64 and is a cause of occupational asthma in humans.65 In mice, papain inhalation increased IL-33 expression in the lung, and subsequently IL-33 induced airway eosinophilia dependently of IL-13 even in the absence of acquired immune cells such as T cells, B cells and NKT cells.64 In addition to IL-33-deficient mice,64 NH cell-depleted mice showed attenuated airway eosinophilia after papain inhalation.66 Thus, lung natural helper cells are crucial for development of papain-induced IL-33-mediated innate-type acute airway eosinophilia. As in mice, resident IL-1RL1-expressing Lin- CD127+ CD25+ NH cells/innate lymphoid cells have been identified in lung parenchymal tissue from healthy humans,53 suggesting that resident NH cells/innate lymphoid cells also may be important for human pulmonary immune responses.

As in asthma, genetic polymorphism of IL-1RL1 has also been identified in patients with atopic dermatitis, and expression of IL-33 is increased in inflamed skin from these patients,21, 67, 68 suggesting involvement of IL-33 in the development of atopic dermatitis. Intradermal injection of IL-33 to mice caused development of skin inflammation accompanied by accumulation of neutrophils.69 In contrast to IL-33-induced airway eosinophilia, the IL-33-induced neutrophilic skin inflammation was dependent on dermal mast cell activation via IL-1RL1.69 The possible roles of basophils and NH cells in IL-33-induced skin inflammation remain poorly understood.

Genetic polymorphism of IL-1RL1 and IL-33 and increased IL-33 levels in specimens are found in certain patients with rhinitis, conjunctivitis and/or rhinosinusitis.70-73 Ovalbumin-induced or ragweed pollen-induced allergic rhinitis is attenuated in anti-IL-33-Ab-treated mice,74 IL-33-deficient mice and FcεRI-deficient mice.73 In ragweed pollen-induced allergic rhinitis, IL-33 enhances release of histamine and chemoattractant factors for eosinophils and basophils by mast cells and basophils, contributing to local inflammation in the early and late phases of diseases.73 IL-1RL1-expressing Lin- CD127+ CD161+ CRTH2+ NH/innate lymphoid cells, which produce IL-13 in response to IL-33 or IL-25 in the presence of IL-2, were identified in the human fetal gut and observed to be accumulated in inflamed, but not non-inflamed, nasal polyps from adult patients with chronic rhinosinusitis.75 Those findings suggest a contribution of IL-33-activated NH/innate lymphoid cells—in addition to mast cells and basophils—to the pathogenesis of allergic diseases.


IL-33 released by such cells as epithelial cells and macrophages after tissue injury during infection plays important roles in host defense against pathogens such as nematodes and viruses by activating various cell types, especially innate-type immune cells, including mast cells, basophils, eosinophils and NH cells/innate lymphoid cells. In addition, dysregulation of IL-33 is suspected to be involved in development of various allergic disorders, such as asthma, dermatitis and rhinitis. Thus, neutralization of IL-33 may be a new therapeutic approach for allergic diseases.


This work was supported by Grants-in-Aid for Young Scientists (A) (S.N.), from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and, PRESTO, JST (S.N.). We also thank Lawrence W. Stiver (Tokyo, Japan) for his critical reading of the manuscript.


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