PP-032 Predictors of mortality in sepsis intensive care unit patients

Background: Glycogen synthase kinase-3 (GSK-3) modulates a wide array of cellular processes including embryonic development, cell differentiation survival and apoptosis. Recently, it was reported that GSK-3 inhibitor functions as an attenuator of LPS-induced septic shock and regulates mortality of endotoxemic mice. However, detailed mechanism of improved mortality via GSK-3 inhibitor was less defined yet. Method: LPS-induced endotoxemia model, Generation and culture of DC, Measurement of Cytokines, Measurement of PMN infiltration. Result: Here, we show that the inhibition of GSK-3 induces ERK1/2 activation in LPS-stressed condition via PKCd activation. These PKCd-induced ERK1/2 activation by the inhibition of GSK-3 provokes IL-10 expression, which has a crucial role as a crucial regulator in endotoxemia condition. We confirmed that GSK-3 inhibition-induced PKCd, ERK1/2 activation provokes IL-10 expression in LPStreated condition using MEK1 and PKCd inhibitor. Next, we observed that septic shock is caused by LPS is attenuated on GSK-3 inhibition using a GSK-3 inhibitor. These relieved endotoxemia induced by GSK-3 inhibition restored in ERK1/2-dependent manner. Conclusion: Taken together, IL-10 expression produced by GSK-3 inhibition-induced ERK activation via PKCd relieves LPS-mediated endotoxemia. This finding suggests that IL-10 hyper-expression-mediated by GSK-3 inhibition-induced ERK activation could be a new therapeutic pathway in the endotoxemial state.