Activation of natural killer T cells contributes to Th1 bias in the murine liver after 14 d of ethinylestradiol exposure  

作　　者：Meng-Zhi Zou Wei-Chao Kong Heng Cai Meng-Tao Xing Zi-Xun Yu Xin Chen Lu-Yong Zhang Xin-Zhi Wang 

机构地区：[1]New Drug Screening Center,China Pharmaceutical University,Nanjing 210009,Jiangsu Province,China [2]Department of Pharmacology,China Pharmaceutical University,Nanjing 210009,Jiangsu Province,China [3]Center for Drug Research and Development,Guangdong Pharmaceutical University,Guangzhou 510006,Guangdong Province,China

出　　处：《World Journal of Gastroenterology》2022年第26期3150-3163,共14页世界胃肠病学杂志（英文版）

基　　金：Supported by the National Natural Science Foundation of China,No.82073948 and 81703626;National Innovation and Entrepreneurship Training Program for Undergraduate,No.202210316040Z。

摘　　要：BACKGROUND As the main component of oral contraceptives(OCs),ethinylestradiol(EE)has been widely applied as a model drug to induce murine intrahepatic cholestasis.The clinical counterpart of EE-induced cholestasis includes women who are taking OCs,sex hormone replacement therapy,and susceptible pregnant women.Taking intrahepatic cholestasis of pregnancy(ICP)as an example,ICP consumes the medical system due to its high-risk fetal burden and the impotency of ursodeoxycholic acid in reducing adverse perinatal outcomes.AIM To explore the mechanisms and therapeutic strategies of EE-induced cholestasis based on the liver immune microenvironment.METHODS Male C57BL/6J mice or invariant natural killer T(iNKT)cell deficiency(Jα18-/-mice)were administered with EE(10 mg/kg,subcutaneous)for 14 d.RESULTS Both Th1 and Th2 cytokines produced by NKT cells increased in the liver skewing toward a Th1 bias.The expression of the chemokine/chemokine receptor Cxcr6/Cxcl16,toll-like receptors,Ras/Rad,and PI3K/Bad signaling was upregulated after EE administration.EE also influenced bile acid synthase Cyp7a1,Cyp8b1,and tight junctions ZO-1 and Occludin,which might be associated with EEinduced cholestasis.iNKT cell deficiency(Jα18-/-mice)robustly alleviated cholestatic liver damage and lowered the expression of the abovementioned signaling pathways.CONCLUSION Hepatic NKT cells play a pathogenic role in EE-induced intrahepatic cholestasis.Our research improves the understanding of intrahepatic cholestasis by revealing the hepatic immune microenvironment and also provides a potential clinical treatment by regulating iNKT cells.

关 键 词：Natural killer T cell Th1/Th2 IFN-γ ESTROGEN CHOLESTASIS 

分 类 号：R965[医药卫生—药理学]