STING-mediated IL-6 Inhibits OATP1B1 Expression via the TCF4 Signaling Pathway in Cholestasis  

作　　者：Yan Guo Hongjia Zhang Nan Zhao Ying Peng Dongya Shen Yubin Chen Xiaoxun Zhang Can-E Tang Jin Chai 

机构地区：[1]Department of Endocrinology,Xiangya Hospital,Central South University,Changsha,Hunan,China [2]Department of Gastroenterology,Institute of Digestive Diseases of PLA,Cholestatic Liver Diseases Center and Center for Metabolic Associated Fatty Liver Disease,The First Affiliated Hospital(Southwest Hospital)to Third Military Medical University(Army Medical University),Chongqing,China [3]Department of Clinical Pharmacology,Xiangya Hospital,Central South University,Changsha,Hunan,China [4]Department of Cardiac Surgery,Xiangya Hospital,Central South University,Changsha,Hunan,China [5]National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha,Hunan,China

出　　处：《Journal of Clinical and Translational Hepatology》2024年第8期701-712,共12页临床与转化肝病杂志（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(82325008,81974112,and 82370642);the Natural Science Foundation of Hunan Province(2024JJ5611);the Outstanding Medical Research Group of Chongqing(414Z381).

摘　　要：Background and Aims Organic anion-transporting polypeptides(OATPs)play a crucial role in the transport of bile acids and bilirubin.In our previous study,interleukin 6(IL-6)reduced OATP1B3 levels in cholestatic disease.However,it remains unclear whether IL-6 inhibits OATP1B1 expression in cholestatic diseases.This study aimed to investigate whether IL-6 can inhibit OATP1B1 expression and explore the underlying mechanisms.Methods The effect of stimulator of interferon genes(STING)signaling on inflammatory factors was investigated in a cholestatic mouse model using RT-qPCR and enzyme-linked immunosorbent assay.To assess the impact of inflammatory factors on OATP1B1 expression in hepatocellular carcinoma,we analyzed OATP1B1 expression by RT-qPCR and Western Blot after treating PLC/PRF/5 cells with TNF-α,IL-1β,and IL-6.To elucidate the mechanism by which IL-6 inhibits OATP1B1 expression,we examined the expression of the OATP1B1 regulator TCF4 in PLC/PRF/5 and HepG2 cells using RT-qPCR and Western Blot.The interaction mechanism betweenβ-catenin/TCF4 and OATP1B1 was investigated by knocking downβ-catenin/TCF4 through siRNA transfection.Results The STING inhibitor decreased inflammatory factor levels in the cholestatic mouse model,with IL-6 exhibiting the most potent inhibitory effect on OATP1B1.IL-6 downregulatedβ-catenin/TCF4,leading to decreased OATP1B1 expression.Knocking-downβ-catenin/TCF4 counteracted theβ-catenin/TCF4-mediated repression of OATP1B1.Conclusions STING-mediated IL-6 up-regulation may inhibit OATP1B1,leading to reduced transport of bile acids and bilirubin by OATP1B1.This may contribute to altered pharmacokinetics in patients with diseases associated with increased IL-6 production.

关 键 词：Inflammation Bile acid BILIRUBIN CHOLESTASIS STING IL-6 β-catenin TCF4 

分 类 号：R575[医药卫生—消化系统]