促炎细胞因子
肝损伤
TLR5型
细胞因子
免疫学
T细胞
免疫系统
生物
医学
炎症
Toll样受体
先天免疫系统
药理学
作者
Lei Wang,Wen Zhang,Chang‐Hui Ge,Rong‐Hua Yin,Xiao Yang,Zhan Yao,Miao Yu,Chang‐Yan Li,Zhiqiang Ge,Xiaoming Yang
出处
期刊:Hepatology
[Wiley]
日期:2017-05-04
卷期号:65 (6): 2059-2073
被引量:34
摘要
Toll‐like receptor‐5 (TLR5) signaling regulates the immune privileged status of the liver and is involved in hepatic immune disorders. However, the role of TLR5 has not yet been investigated in experimental models of concanavalin A (Con A)–mediated liver injury. Here, we show that TLR5 is highly up‐regulated in the hepatic mononuclear cells of mice during Con A–induced hepatitis. Increased mortality and liver histopathology of TLR5‐deficient mice correlated with excessive production of proinflammatory cytokines, suggesting that TLR5 knockout mice were more susceptible to Con A–induced hepatitis. We also report that administration of CBLB502, an exogenous TLR5 agonist, substantially alleviated Con A–mediated hepatitis in wild‐type mice as shown by increased survival rates, reduced aminotransferase and proinflammatory cytokine production, impaired lymphocyte infiltration, and ameliorated hepatocyte necrosis and/or apoptosis. Mechanistic studies revealed that CBLB502 acts as a negative regulator in limiting T‐cell/natural killer T‐cell activity and cytokine production in the Con A–hepatitis model. Bone marrow transplantation experiments showed that TLR5 in bone marrow–derived cells contributed to the hepatoprotective efficacy of CBLB502 against Con A–induced liver injury. Moreover, interleukin‐6 elevation induced by CBLB502 is an important protective factor against Con A–induced liver injury. In addition, we demonstrate that CBLB502 suppresses α‐galactosylceramide‐induced natural killer T cell–dependent inflammatory liver injury. Conclusion : The TLR5 signaling pathway plays an important role in T cell–mediated hepatic injury and may be exploited for therapeutic treatment of inflammatory liver diseases. (H epatology 2017;65:2059‐2073).
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