Cutting edge: Endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface Toll-like receptor 4 expression

Monocytes/macrophages exposed to LPS show reduced responses to second stimu lation with LPS, which is termed LPS tolerance, In this study, we investiga ted molecular mechanism of LPS tolerance in macrophages, Mouse peritoneal m acrophages pre-exposed to LPS exhibited reduced production of inflammatory cytokines in a time- and dose-dependent manner. Activation of neither IL-1 receptor-associated kinase nor NF-kappa B was observed in macrophages that became tolerant by LPS pretreatment, indicating that the proximal event in Toll-like receptor 4 (TLR4)-MyD88-dependent signaling is affected in tolera nt macrophages. Although TLR4 mRNA expression significantly decreased withi n a few hours of LPS pretreatment and returned to the original level at 24 h, the surface TLR4 expression began to decrease within 1 h, with a gradual decrease after that, and remained suppressed over 24 h, A decrease in infl ammatory cytokine production in tolerant macrophages well correlates with d own-regulation of the surface TLR4 expression, which may explain one of the mechanisms for LPS tolerance.