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.