Wang Xinzhi, Jiang Zhenzhou, Xing Mengtao, Fu Jing, Su Yuwen, Sun Lixin, Zhang Luyong
Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, 24 Tong Jia Xiang, Nanjing 210009, PR China.
Food Chem Toxicol. 2014 Sep;71:33-41. doi: 10.1016/j.fct.2014.06.004. Epub 2014 Jun 17.
Triptolide (TP)-induced liver injury can be attributed to the Th17/Treg imbalance with the enhancement of the expansion of Th17 cells and suppression of the production of Tregs, especially the significant increase of interleukin (IL)-17 secreted by helper T (Th) 17 cells. To further investigate the involvement of IL-17-mediated immune response in the TP-induced hepatotoxicity, we examined the plasma transaminase, histopathological changes, hepatic frequencies of Th17 cells, hepatic expression of transcriptional factors and cytokines genes and plasma IL-17 levels after administration of TP (600 μg/kg) by oral gavage to female C57BL/6 mice. Mice treated with TP displayed acute liver injury with significantly increased hepatic frequencies of Th17 cells, mRNA expression of retinoid-related orphan receptor (ROR)-γt and plasma IL-17 level as well as the plasma ALT and AST. Neutralization study using anti-IL-17 antibody ameliorated TP-induced liver injury. In contrast, when challenged by coadministration of recombinant IL-17, hepatotoxicity was exacerbated in the triptolide-administered mice. In summary, this report was demonstrated for the first time that IL-17-mediated immune response is involved in the pathogenesis of TP-induced liver injury in mice, which may shed light on the mechanisms of TP-induced liver injury.
雷公藤甲素（TP）诱导的肝损伤可归因于Th17/Treg失衡，即Th17细胞扩增增强以及Tregs产生受到抑制，尤其是辅助性T（Th）17细胞分泌的白细胞介素（IL）-17显著增加。为了进一步研究IL-17介导的免疫反应在TP诱导的肝毒性中的作用，我们通过对雌性C57BL/6小鼠经口灌胃给予TP（600μg/kg），检测了血浆转氨酶、组织病理学变化、肝脏中Th17细胞的频率、转录因子和细胞因子基因的肝脏表达以及血浆IL-17水平。用TP处理的小鼠表现出急性肝损伤，肝脏中Th17细胞的频率、维甲酸相关孤儿受体（ROR）-γt的mRNA表达、血浆IL-17水平以及血浆谷丙转氨酶（ALT）和谷草转氨酶（AST）均显著增加。使用抗IL-17抗体的中和研究减轻了TP诱导的肝损伤。相反，当联合给予重组IL-17进行刺激时，雷公藤甲素处理的小鼠肝毒性加剧。总之，本报告首次证明IL-17介导的免疫反应参与了小鼠TP诱导的肝损伤发病机制，这可能为TP诱导肝损伤的机制提供线索。
