Staphylococcus aureus Induces Microglial Inflammation via a Glycogen Synthase Kinase 3β-Regulated Pathway

A proinflammatory role for glycogen synthase kinase 3 beta (GSK-3 beta) has been demonstrated. Here, we addressed its roles on heat-inactivated Staphylococcus aureus-induced microglial inflammation. Heat-inactivated S. aureus induced tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO) production, at least in part, via a Toll-like receptor 2-regulated pathway. Neutralization of TNF-alpha largely blocked heat-inactivated S. aureus-induced NO. Heat-inactivated S. aureus activated GSK-3 beta, and inhibiting GSK-3 beta reduced TNF-alpha production as well as inducible NO synthase (iNOS)/NO biosynthesis. While activation of NF-kappa B was essential for heat-inactivated S. aureus-induced TNF-alpha and NO, inhibiting GSK-3 beta blocked heat-inactivated S. aureus-induced NF-kappa B p65 nuclear translocation. Additionally, inhibiting GSK-3 beta enhanced heat-inactivated S. aureus-induced interleukin-10 (IL-10) production (IL-10 is an anti-inflammatory cytokine which inhibits TNF-alpha production). Neutralization of IL-10 reduced TNF-alpha downregulation caused by GSK-3 beta inhibition. These results suggest that GSK-3 beta regulates heat-inactivated S. aureus-induced TNF-alpha and NO production in microglia mainly by activating NF-kappa B and probably by inhibiting IL-10.