The role of invariant natural killer T cells and associated immunoregulatory factors in triptolide-induced cholestatic liver injury. (December 2020)

• Record Type: Journal Article
• Authors: Zou, Mengzhi; Nong, Cheng; Yu, Zixun; Cai, Heng; Jiang, Zhenzhou; Xue, Rufeng; Huang, Xin; Sun, Lixin; Zhang, Luyong; Wang, Xinzhi
• Is Part Of: Food and chemical toxicology. Volume 146(2020)
• Publication Date: 2020-12
• Subjects: iNKT cell -- Triptolide -- Cholestasis -- Th1/Th2 cytokines -- Bile acid; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2020.111777
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Proinflammatory cytokines are potent inhibitors of bile acid nuclear receptors and transporters. Triptolide (TP), an active ingredient of Tripterygium wilfordii Hook. f ., exhibits unique efficacy for autoimmune diseases and tumors. While its clinical application is greatly constrained by hepatotoxicity. Therefore, we explored the mechanism of iNKT cells and associated immunoregulators in TP-induced cholestatic liver injury. TP was administered to both female C57BL/6 mice and Jα18 −/− mice. INKT cells released significantly increased Th2 cytokine IL-4 in C57BL/6 mice after TP administration. Blood biochemistry, histopathology and immunohistochemistry demonstrated that TP-induced cholestasis liver injury. In Jα18 −/− mice, cholestatic liver damage was alleviated due to the upregulation of type 2 NKT cells, nuclear receptor FXR, transporter OATP1B2 and CYP450, but also the downregulation of Cxcl10, ICAM-1 and Egr-1. Above results suggested that Th2 cytokines produced by iNKT cells suppressed type 2 NKT cells and promoted the expression of immunoregulatory factors represented by CXCL10, ICAM-1 and Egr-1, which in turn affected cholestasis-related nuclear receptor, transporter and enzymes, thus aggravated cholestatic liver injury. Our research contributes to better understanding of the role of iNKT cells in TP-induced cholestatic liver injury, thereby providing potential therapeutic targets for clinical prevention and treatment. Graphical abstract: Image 1 Highlights: INKT cells involve in TP-induced cholestatic liver injury by inducing inflammation. INKT cells produce Th2 cytokines to induce CXCL10, ICAM-1 and Egr-1 expression. Jα18 −/− mice inhibited CXCL10, ICAM-1 and Egr 1, leading to TP toxicity mitigation. Jα18 −/− mice upregulated type 2 NKT cells, FXR, OATP1B2 and CYP450 to improve cholestasis of TP. NKT cell and related immunoregulatory factors provide targets for cholestasis.