雷公藤多苷增强肝脏对炎性刺激敏感性诱发肝损伤的机制研究

雷公藤多苷（GTW）是从中药雷公藤去皮根部提取的总苷，通过免疫抑制作用发挥药效。然而免疫抑制在GTW所致肝损伤中的作用尚不明确。本课题组前期工作发现，GTW预处理可以使无毒性剂量的LPS产生严重的肝毒性，表明肝脏对炎性刺激的敏感性显著增强。同时，研究发现GTW可以抑制Caspase 8拮抗因子cFLIP的蛋白表达，提示GTW可能通过破坏肝细胞促存活和促死亡信号通路之间的平衡，致使肝脏免疫应答功能失常，无法抵抗炎性刺激而诱导肝细胞死亡。因此，课题组提出如下假设：GTW通过抑制抗凋亡因子cFLIP的蛋白表达抑制促存活信号通路，破坏肝细胞耐受性免疫应答，增强肝脏对炎性刺激的敏感性，导致肝损伤显著加重。本研究预期阐明GTW通过破坏肝脏免疫应答功能增加肝脏受损风险的分子机制，研究结果对于理解GTW经免疫抑制介导的肝毒性机制具有重要的科学意义，为GTW制剂在临床的安全合理应用提供理论依据。

Tripterygium wilfordii multiglycoside (GTW), an extract derived from T. wilfordii, has been used for rheumatoid arthritis and other immune diseases in China. Although immunosuppression is regarded as a primary active effect of GTW, there is no research focusing on the role of immunosuppression in GTW-induced liver injury. Our previous research indicated that LPS administration induced severe acute hepatocyte death when mice were pre-treated with GTW, suggesting that liver sensitivity to inflammatory stimuli was enhanced. Moreover, we found that the protein level of cFLIP after GTW administration was inhibited significantly, which may destroy the balance between pro-survival and pro-death signaling pathways. Due to the disfunction of liver immune response, the inflammatory stimuli could induce hepatocyte death. Thus, we propose the following hypothesis: GTW destroyed the pro-survival signaling pathway by inhibiting the hepatocytic protective protein cFLIP, increasing the sensitivity of liver to inflammatory stimulation, which finally enhanced liver damage. After all, this study aimed to clarify the mechanism on GTW-induced liver injury associated with the inhibition of liver immune response, which may provide a new perspective to GTW-induced liver injury and benefit to the clinical treatment of GTW.