The ST2 gene produces a soluble secreted form and a transmembrane form, referred to as soluble ST2 and ST2L, respectively. A recent study has reported that interleukin (IL)-33 is a specific ligand of ST2L and induces production of T helper type 2 (Th2) cytokines. Although soluble ST2 is highly produced in sera of asthmatic patients and plays a critical role for production of Th2 cytokines, the function of soluble ST2 in relation to IL-33 signaling remains unclear. Here we show antagonistic effects of soluble ST2 on IL-33 signaling using a murine thymoma EL-4 cells stably expressing ST2L and a murine model of asthma. Soluble ST2 directly bound to IL-33 and suppressed activation of NF-B in EL-4 cells stably expressing ST2L, suggesting that the complex of soluble ST2 and IL-33 fails to bind to ST2L. In a murine model of asthma, pretreatment with soluble ST2 reduced production of IL-4, IL-5, and IL-13 from IL-33-stimulated splenocytes. These results indicate that soluble ST2 acts as a negative regulator of Th2 cytokine production by the IL-33 signaling. Our study provides a molecular mechanism wherein soluble ST2 modulates the biological activity of IL-33 in allergic airway inflammation.The interleukin (IL)-1 2 receptor family plays important roles in inflammatory and immunological responses. The ST2 gene is a member of the IL-1 receptor family, producing a soluble secreted form and a transmembrane form, soluble ST2 and ST2L, respectively (1-3). These proteins are generated by alternative splicing of pre-mRNA. The structure of ST2L is similar to that of IL-1 receptor type I (IL-1RI), consisting of three extracellular immunoglobulin domains and an intracellular Tollinterleukin-1 receptor domain. Although the extracellular domain is common to soluble ST2 and ST2L, soluble ST2 lacks the transmembrane and intracellular Toll-interleukin-1 receptor domains. The ST2 gene is expressed in several cells including fibroblasts and mast cells (1, 4). In particular, ST2L is preferentially expressed in murine and human Th2 cells and can be utilized as a specific marker of Th2 cells in in vitro experiments (5-8). Therefore, the function of ST2L has been suggested to correlate with Th2 cell-mediated immunological responses. However, ST2L has been an orphan receptor ever since it was first reported (5). Late in 2005, IL-33, a newly discovered member of the IL-1 cytokine family, was finally reported as a specific ligand for ST2L (9).The IL-33 gene, also described as a nuclear factor expressed in high endothelial venules (NF-HEV) (10), codes a 31-kDa protein that does not contain a signal sequence for secretion, similar to the IL-1␣, IL-1␤, and IL-18 genes (11,12). Previous study has demonstrated the processing and function of the IL-33 protein (9). The precursor 31-kDa protein (pre-IL-33) was cleaved by caspase-1 into a mature 18-kDa protein (IL-33) in in vitro experiments using a recombinant protein. Functional analysis has shown that IL-33 bound to murine mast cells expressing ST2L and stimulated the intracellular signaling pathway,...

IL-33 levels were elevated in sera and SF samples from patients with RA, and correlated with disease activity. IL-33 was produced mainly in inflamed joints; IL-33/ST2L signaling might play an important role in joint inflammation of human RA.

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Using a yeast two-hybrid screen, we found that SNIP1 (Smad nuclear-interacting protein 1) associates with c-Myc, a key regulator of cell proliferation and transformation. We demonstrate that SNIP1 functions as an important regulator of c-Myc activity, binding the N terminus of c-Myc through its own C terminus, and that SNIP1 enhances the transcriptional activity of c-Myc both by stabilizing it against proteosomal degradation and by bridging the c-Myc/p300 complex. These effects of SNIP1 on c-Myc likely contribute to synergistic effects of SNIP1, c-Myc, and H-Ras in inducing formation of foci in an in vitro transformation assay and also in supporting anchorage-independent growth. The significant association of SNIP1 and c-Myc staining in a non-small cell lung cancer tissue array is further evidence that their activities might be linked and suggests that SNIP1 might be an important modulator of c-Myc activity in carcinogenesis.