IntroductionCytokines of the interleukin (IL)-1 family are major proinflammatory and immunoregulatory mediators that act through receptors of the Toll-like/IL-1-receptor (TLR/IL-1R) superfamily. Due to homologous intracellular Toll/interleukin-1 receptor (TIR) domains, IL-1 family members and TLR-ligands activate very similar signaling pathways leading to NF-B-and MAPKactivation. 1 IL-1␣ and IL-1␤, the prototypic family members, are generated in response to exogenous and endogenous danger signals and act as chief inflammatory mediators in many inflammatory conditions. 2 Recent studies indicate that IL-1 may also participate in inflammatory pathologies and auto-immune diseases involving Th17-type T-helper cells. [3][4][5] By contrast, IL-18 is best known for its role in Th1-type immune responses because it strongly amplifies IFN-␥ production in natural killer (NK) cells and Th1 cells in synergy with However, several lines of evidence mainly derived from mouse models indicate that IL-18 can also play a role in allergic diseases and defense against helminths. 6,7 For example, in the absence of IFN-␥ signaling, IL-18 increases immunoglobulin E (IgE) levels and promotes a Th2-type pathology. 8 It has been suggested that this is due to the antigen-independent action of IL-18 on cells of the "innate allergic response," basophils and mast cells. 7 Bone marrow-derived c-Kit Ϫ /Fc⑀RI ϩ mouse "basophil-like" cells express IL-18 receptors (IL-18R), and IL-18 induces IL-4 and IL-13 expression in an antigen-independent manner as efficiently as In the human system, IL-18 primes basophilic KU812 cells for enhanced leukotriene C 4 (LTC 4 ) production. 9 Furthermore, a recent screen of novel CD antigens revealed that blood basophils express IL-18R and IL-18R-accessory protein (IL-18Rap), 10 indicating that IL-18 may also act on human basophils.A soluble form of an IL-1R family member ST2 (sST2; also called T1) has been cloned many years ago. sST2 is formed by many cells and increased sST2 levels are found in inflammatory conditions, including allergic asthma. [11][12][13] The expression of transmembrane ST2-receptor (ST2L), however, is largely restricted to cells of hematopoietic origin. ST2L is expressed by mouse bone marrow-derived mast cells (BMMCs) and is a stable marker of mouse, but not human, Th2-lymphocytes. [14][15][16][17] In the absence of a known ligand, the biologic roles of ST2 have been extensively studied in several mouse models using ST2-antibodies, sST2-constructs, and ST2-KO-mice. 14,18 Although the interpretations were sometimes conflicting, most studies indicate an important contribution of ST2 in Th2-type immune responses and allergic inflammation. The biology of ST2 is further complicated by a possible direct antiinflammatory action of sST2, and by the fact that the TIR domain of ST2L appears to be a negative regulator of 20 Research on ST2 strongly gained momentum by the recent discovery of its ligand, the novel IL-1 family member IL-33. 21 Like IL-1␣, the human IL-33 precursor (proIL-33) is a nuclear pr...