The role of invariant natural killer T cells and associated immunoregulatory factors in triptolide-induced cholestatic liver injury.
The role of invariant natural killer T cells and associated immunoregulatory factors in triptolide-induced cholestatic liver injury.
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DOI：
10.1016/j.fct.2020.111777
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发表时间：
2020-09
期刊：
影响因子：
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通讯作者：
Mengzhi Zou;Cheng Nong;Zixun Yu;Heng Cai;Zhenzhou Jiang;Rufeng Xue;Xin Huang;Lixin Sun
中科院分区：
文献类型：
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作者：
Mengzhi Zou;Cheng Nong;Zixun Yu;Heng Cai;Zhenzhou Jiang;Rufeng Xue;Xin Huang;Lixin Sun
促炎细胞因子是胆汁酸核受体和转运体的有效抑制剂。雷公藤甲素（TP），雷公藤属植物的有效成分。F .对自身免疫性疾病和肿瘤表现出独特的疗效。但其临床应用受到肝毒性的极大限制。因此，我们探讨了iNKT细胞及其相关免疫调节因子在tp诱导的胆汁淤积性肝损伤中的作用机制。雌性C57BL/6小鼠和Jα18−/−小鼠均给予TP。TP给药后，C57BL/6小鼠的INKT细胞释放的Th2细胞因子IL-4显著增加。血液生化、组织病理学和免疫组织化学证实tp诱导的胆汁淤积性肝损伤。在Jα18−/−小鼠中，由于2型NKT细胞、核受体FXR、转运体OATP1B2和CYP450的上调，以及cxcl10、ICAM-1和Egr-1的下调，胆汁淤积性肝损伤得到缓解。以上结果提示，iNKT细胞产生的Th2细胞因子抑制2型NKT细胞，促进以CXCL10、ICAM-1、Egr-1为代表的免疫调节因子的表达，进而影响胆汁淤积相关的核受体、转运体和酶，从而加重胆汁淤积性肝损伤。我们的研究有助于更好地了解iNKT细胞在tp诱导的胆汁淤积性肝损伤中的作用，从而为临床预防和治疗提供潜在的治疗靶点。
Proinflammatory cytokines are potent inhibitors of bile acid nuclear receptors and transporters. Triptolide (TP), an active ingredient ofTripterygium wilfordiiHook. 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 ofCxcl10, 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.