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Báo cáo y học: "Fas (CD95) induces rapid, TLR4/IRAK4-dependent release of pro-inflammatory HMGB1 from macrophages"

Tuyển tập báo cáo các nghiên cứu khoa học quốc tế ngành y học dành cho các bạn tham khảo đề tài: Fas (CD95) induces rapid, TLR4/IRAK4-dependent release of pro-inflammatory HMGB1 from macrophages. | Wang et al. Journal of Inflammation 2010 7 30 http www.journal-inflammation.eom content 7 1 30 JOURNAL OF INFLAMMATION RESEARCH Open Access Fas CD95 induces rapid TLR4 IRAK4-dependent release of pro-inflammatory HMGB1 from macrophages Feng Wang 1 Ziyue Lu1 Michael Hawkes1 Huan Yang2 Kevin C Kain1 and W Conrad Liles 1 Abstract Although Fas CD95 is recognized as a death receptor that induces apoptosis recent studies indicate that the Fas FasL system can induce pro-inflammatory cytokine production by macrophages independent of conventional caspase-mediated apoptotic signaling. The precise mechanism s by which Fas activates macrophage inflammation is unknown. We hypothesized that Fas stimulates rapid release of high mobility group box 1 HMGB1 that acts in an autocrine and or paracrine manner to stimulate pro-inflammatory cytokine production via a Toll-like receptor-4 TLR4 Interleukin-1 receptor associated kinase-4 IRAK4 -dependent mechanism. Following Fas activation HMGB1 was released within 1 hr from viable RAW267.4 cells and primary murine peritoneal macrophages. HMGB1 release was more rapid following Fas activation compared to LPS stimulation. Neutralization of HMGB1 with an inhibitory anti-HMGB1 monoclonal antibody strongly inhibited Fas-induced production of tumor necrosis factor TNF and macrophage inflammatory protein-2 MIP-2 . Both Fas-induced HMGB1 release and associated pro-inflammatory cytokine production were significantly decreased from Tlr4- - and ưak4 - macrophages but not Tlr2- - macrophages. These findings reveal a novel mechanism underlying Fas-mediated pro-inflammatory physiological responses in macrophages. We conclude that Fas activation induces rapid TLR4 IRAK4-dependent release of HMGB1 that contributes to Fas-mediated pro-inflammatory cytokine production by viable macrophages. Introduction Fas CD95 is a 48-kDa type I transmembrane protein member of the TNF receptor family 1 . The endogenous ligand for Fas is FasL CD178 a 40-kDa type II .