Ursodeoxycholic acid and 18β-glycyrrhetinic acid alleviate ethinylestradiol-induced cholestasis via downregulating RORγt and CXCR3 signaling pathway in iNKT cells

Abstract

Estrogen-induced intrahepatic cholestasis (IHC) is a mild but potentially serious risk and urges for new therapeutic targets and effective treatment. Our previous study demonstrated that RORγt and CXCR3 signaling pathway of invariant natural killer T (iNKT) 17 cells play pathogenic roles in 17α-ethinylestradiol (EE)-induced IHC. Ursodeoxycholic acid (UDCA) and 18β-glycyrrhetinic acid (GA) present a protective effect on IHC partially due to their immunomodulatory properties. Hence in present study, we aim to investigate the effectiveness of UDCA and 18β-GA in vitro and verify the accessibility of the above targets. Biochemical index measurement indicated that UDCA and 18β-GA presented efficacy to alleviate EE-induced cholestatic cytotoxicity. Both UDCA and 18β-GA exhibited suppression on the CXCL9/10-CXCR3 axis, and significantly restrained the expression of RORγt in vitro. In conclusion, our observations provide new therapeutic targets of UDCA and 18β-GA, and 18β-GA as an alternative treatment for EE-induced cholestasis.

Keywords: 18β-glycyrrhetinic acid; CXCR3; Ethinylestradiol-induced cholestasis; RORγt; UDCA; iNKT17 cell.