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 cellmediated 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 antigenspecific 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.asthma | colitis | cytokine | interleukin-33 | sepsis

SUMMARY House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient KitW-sh/W-sh mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells.

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Interleukin-33 (IL-33) is a member of the IL-1 cytokine family, which includes IL-1 and IL-18, and is considered to be important for host defense against nematodes by inducing Th2 cytokine production via the IL-33 receptor. IL-33 receptor is a heterodimer of IL-1 receptor-like 1 (IL-1RL1; also called ST2, T1, Der4, and fit-1) and IL-1 receptor accessory protein (IL-1RAcP). On the other hand, excessive and/or inappropriate production of IL-33 is considered to be involved in the development of various disorders, such as allergic and autoimmune diseases. Unlike IL-1b and IL-18, IL-33 does not seem to be secreted through the activation of inflammasomes in events such as apoptosis. However, IL-33 is localized in the nucleus of cells and is released during tissue injury associated with necrosis. This suggests that it acts as an alarmin, like IL-1a and high-mobility group box chromosomal protein-1 (HMGB-1). This review summarizes current knowledge regarding the roles of IL-33 in the functions of various cell types and the pathogenesis of allergy.

IL-17A, IL-17F and IL-25 are ligands for IL-17RA. In the present study, we demonstrated that IL-25-deficient mice, but not IL-17A-, IL-17F-, IL-17A/F-, IL-23p19- and ROR-γt-deficient mice, showed significant suppression of the number of eosinophils and the levels of proinflammatory mediators in bronchoalveolar lavage fluids, airway hyperresponsiveness to methacholine, or ovalbumin-specific IgG1 and IgE levels in the serum during ovalbumin-induced Th2-type/eosinophilic airway inflammation, without any effect on lung DC migration or antigen-specific memory-Th2-cell expansion during antigen sensitization. By adoptive transfer of either T cells, mast cells or bone marrow cells from IL-25-deficient mice, we found that IL-25 produced by airway structural cells such as epithelial cells—but not by such hematopoietic stem-cell-origin immune cells as T cells and mast cells—was indispensable for induction of Th2-type/eosinophilic airway inflammation by activating lung epithelial cells and eosinophils. Therefore, airway structural-cell-derived IL-25—rather than Th17-cell-derived IL-17A and IL-17F—is responsible for induction of local inflammation by promoting activation of lung epithelial cells and eosinophils in the elicitation phase—but is not required for antigen-specific Th2 cell differentiation in the sensitization phase—of Th2-type/eosinophilic airway inflammation.

IL-31, which is a member of the IL-6 family of cytokines, is produced mainly by activated CD4+ T cells, in particular activated Th2 cells, suggesting a contribution to development of type-2 immune responses. IL-31 was reported to be increased in specimens from patients with atopic dermatitis, and IL-31-transgenic mice develop atopic dermatitis-like skin inflammation, which is involved in the pathogenesis of atopic dermatitis. However, the role of IL-31 in development of contact dermatitis/contact hypersensitivity (CHS), which is mediated by hapten-specific T cells, including Th2 cells, is not fully understood. Therefore, we investigated this using IL-31-deficient (Il31−/−) mice, which we newly generated. We demonstrated that the mice showed normal migration and maturation of skin dendritic cells and induction of hapten-specific T cells in the sensitization phase of FITC-induced CHS, and normal induction of local inflammation in the elicitation phase of FITC- and DNFB-induced CHS. On the other hand, those mice showed reduced scratching frequency and duration during FITC- and/or DNFB-induced CHS. Our findings suggest that IL-31 is responsible for pruritus, but not induction of local skin inflammation, during CHS induced by FITC and DNFB.

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.

BackgroundIL-33, a member of the IL-1 family of cytokines, provokes Th2-type inflammation accompanied by accumulation of eosinophils through IL-33R, which consists of ST2 and IL-1RAcP. We previously demonstrated that macrophages produce IL-33 in response to LPS. Some immune responses were shown to differ between ST2-deficient mice and soluble ST2-Fc fusion protein-treated mice. Even in anti-ST2 antibody (Ab)-treated mice, the phenotypes differed between distinct Ab clones, because the characterization of such Abs (i.e., depletion, agonistic or blocking Abs) was unclear in some cases.Methodology/Principal FindingsTo elucidate the precise role of IL-33, we newly generated neutralizing monoclonal Abs for IL-33. Exogenous IL-33 potentiated LPS-mediated cytokine production by macrophages. That LPS-mediated cytokine production by macrophages was suppressed by inhibition of endogenous IL-33 by the anti-IL-33 neutralizing mAbs.Conclusions/SignificanceOur findings suggest that LPS-mediated macrophage activation is accelerated by macrophage-derived paracrine IL-33 stimulation.