Staphylococcus aureus induces microglial inflammation via a glycogen synthase kinase 3beta-regulated pathway.
A proinflammatory role for glycogen synthase kinase 3beta (GSK-3beta) 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-3beta, and inhibiting GSK-3beta reduced TNF-alpha production as well as inducible NO synthase (iNOS)/NO biosynthesis. While activation of NF-kappaB was essential for heat-inactivated S. aureus-induced TNF-alpha and NO, inhibiting GSK-3beta blocked heat-inactivated S. aureus-induced NF-kappaB p65 nuclear translocation. Additionally, inhibiting GSK-3beta 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-3beta inhibition. These results suggest that GSK-3beta regulates heat-inactivated S. aureus-induced TNF-alpha and NO production in microglia mainly by activating NF-kappaB and probably by inhibiting IL-10.
Cheng
Yi-Lin
YL
Institute of Clinical Medicine, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan.
Wang
Chi-Yun
CY
Huang
Wei-Ching
WC
Tsai
Cheng-Chieh
CC
Chen
Chia-Ling
CL
Shen
Ching-Fen
CF
Chi
Chia-Yu
CY
Lin
Chiou-Feng
CF
D000818:Animals; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D016753:Interleukin-10 / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology*; D013211:Staphylococcus aureus / Q000472:pathogenicity*; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016328:NF-kappa B; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3