A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of toll-like receptor 4 expression

ST2/ST2L, a member of the IL-1R gene family, is expressed by fibroblasts, m ast cells, and Th2, but not Th1, cells. It exists in both membrane-bound (S T2L) and soluble forms (ST2). Although ST2L has immunoregulatory properties , its ligand, cellular targets, and mode of action remain unclear. Using a soluble ST2-human IgG fusion protein, Nye demonstrated that ST2 bound to pr imary bone marrow-derived macrophages (BMM) and that this binding was enhan ced by treatment with LPS. The sST2 treatment of BMMs inhibited production of the LPS-induced proinflammatory cytokines IL-6, IL-12, and TNF-alpha but did not alter IL-10 or NO production. Treatment of BMMs with sST2 down-reg ulated expression of Toll-like receptors-4 and -1 but induced nuclear trans location of NF-kappaB Administration of sST2 in vivo after LPS challenge si gnificantly reduced LPS-mediated mortality and serum levels of IL-6, IL-12, and TNF-alpha. Conversely, blockade of endogenous ST2 through administrati on of anti-ST2 Ab exacerbated the toxic effects of LPS. Thus, ST2 has anti- inflammatory properties that act directly on macrophages. We demonstrate he re a novel regulatory pathway for LPS-induced shock via the ST2-Toll-like r eceptor 4 route. This may be of considerable therapeutic potential for redu cing the severity and pathology of inflammatory diseases.