Protein kinase C delta (PKCδ)−extracellular-signal regulated kinase 1/2 (ERK1/2) signaling cascade regulates glycogen synthase kinase-3 (GSK-3) inhibition−mediated interleukin-10 (IL-10) expression in lipopolysaccharide (LPS)−induced endotoxemia (IRM5P.704)

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 a GSK-3 inhibitor attenuates lipopolysaccharide (LPS)−induced septic shock and regulates the mortality of endotoxemic mice. However, the detailed mechanism of reduced mortality via GSK-3 inhibition is not well defined. Herein, we showed that GSK-3 inhibition induces extracellular-signal regulated kinase 1/2 (ERK1/2) activation under LPS−stressed conditions via protein kinase C delta (PKCδ) activation. Furthermore, PKCδ−induced ERK1/2 activation by the inhibition of GSK-3 provoked the production of interleukin (IL)-10, playing a crucial role in regulating endotoxemia. Using a mitogen-activated protein kinase kinase-1 (MEK-1) and PKCδ inhibitor, we confirmed that GSK-3 inhibition induces PKCδ and subsequent ERK1/2 activation, resulting in increased IL-10 expression under LPS−treated conditions. We verified that septic shock caused by LPS is attenuated by GSK-3 inhibition using a GSK-3 inhibitor. This relieved endotoxemia induced by GSK-3 inhibition restored in ERK1/2−dependent manner. Taken together, IL-10 expression produced by GSK-3 inhibition−induced ERK1/2 activation via PKCδ relieved LPS−mediated endotoxemia. This finding suggests that IL-10 hyper-expression resulted from GSK-3 inhibition−induced ERK activation could be a new therapeutic pathway for endotoxemia.