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Posters-Accepted Abstracts: J Clin Cell Immunol
Sepsis is triggered by bacterial infection, with the most lethal form (endotoxic shock) being caused by lipopolysaccharide (LPS) released from the replicating Gram-negative bacteria into the circulation, where it is recognized by various innate immune cells including macrophages. The interaction of LPS with macrophages triggers the production of various proinflammatory cytokines including IL-6 and thereby contributes to the pathogenesis of sepsis. The production of IL-6 is a hallmark of sepsis, with high levels of this cytokine in individuals with septic mortality. IL-6 is thus a potential marker for the severity of systemic bacterial infection . Despite the central role of IL-6 production in sepsis, however, the signaling mechanisms responsible for triggering IL-6 production by LPS in macrophages have still remained unclear. We have now shown that LPS-induced IL-6 synthesis in macrophages is significantly contributed by an autocrine-/paracrine-acting BLT2-linked cascade. Consistent with this role for BLT2 in LPS signaling to IL-6 production, we found that the abundance of BLT2 mRNA in mouse lung tissue was increased in response to i.p. administration of LPS, and that treatment with the BLT2 inhibitor markedly ameliorated septic lung inflammation and mortality associated with LPS-induced sepsis.