Wang Xinzhi, Jiang Zhenzhou, Cao Weiping, Yuan Ziqiao, 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.
Fitoterapia. 2014 Mar;93:245-51. doi: 10.1016/j.fitote.2014.01.006. Epub 2014 Jan 18.
The study was designed to investigate the immune-modulatory effects of triptolide (TP) on CD4(+) T cell responses during liver injury. Previous studies have suggested that TP plays a critical role in modulating both innate and adaptive immune reactions, but its effects on the Th17/Treg balance during TP-induced liver injury remain unknown. In this study, female C57BL/6 mice were administered by oral gavage with TP at a dose of 250 or 500 μg/kg per mouse. We examined the plasma biochemical parameters, histopathological changes, hepatic frequencies of Th17 cells and Treg cells, hepatic expression of transcriptional factors and cytokine genes and hepatic interleukin (IL)-17 and IL-10 levels in TP-administered mice. Mice treated with TP displayed liver injury with markedly increased plasma transaminase as well as hepatic mRNA expression of retinoid related orphan receptor (ROR)-γt and hepatic IL-17 level at 24h. However, hepatic frequencies of Tregs and hepatic expression of forkhead/winged-helix family transcriptional repressor p3 (FoxP3) decreased at 24h after TP administration. Furthermore, we found that elevated serum biochemical parameters positively correlated with the Th17/Treg ratios. Taken together, these results revealed a novel and interesting phenomenon of TP in the enhancement of the expansion of Th17 cells and suppression of the production of Tregs during liver injury, which may represent a new pathogenesis of TP-induced liver injury.
本研究旨在探讨雷公藤甲素（TP）在肝损伤过程中对CD4(+) T细胞反应的免疫调节作用。先前的研究表明，TP在调节先天性和适应性免疫反应中起关键作用，但其在TP诱导的肝损伤过程中对Th17/Treg平衡的影响尚不清楚。在本研究中，对雌性C57BL/6小鼠经口灌胃给予TP，剂量为每只小鼠250或500μg/kg。我们检测了给予TP的小鼠的血浆生化参数、组织病理学变化、Th17细胞和Treg细胞的肝脏频率、转录因子和细胞因子基因的肝脏表达以及肝脏白细胞介素（IL）-17和IL-10水平。给予TP治疗的小鼠在24小时时出现肝损伤，血浆转氨酶以及类视黄醇相关孤儿受体（ROR）-γt的肝脏mRNA表达和肝脏IL-17水平显著升高。然而，在给予TP后24小时，Tregs的肝脏频率和叉头/翼状螺旋家族转录抑制因子p3（FoxP3）的肝脏表达降低。此外，我们发现升高的血清生化参数与Th17/Treg比率呈正相关。综上所述，这些结果揭示了TP在肝损伤过程中增强Th17细胞扩增和抑制Tregs产生的一种新的有趣现象，这可能代表了TP诱导肝损伤的一种新发病机制。
