Article

Activation of natural killer T cells contributes to triptolide-induced liver injury in mice

Authors: Xin-zhi Wang1, Ru-feng Xue2, Shen-ye Zhang3, Ya-ting Zheng1, Lu-yong Zhang1,4, Zhen-zhou Jiang1,5
1 Jiangsu Key Laboratory of Drug Screening, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
2 CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230027, China
3 Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
4 Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing 210009, China
5 Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Nanjing 210009, China
Correspondence to: Lu-yong Zhang: lyzhang@cpu.edu.cn, Zhen-zhou Jiang: beaglejiang@cpu.edu.cn,
DOI: 10.1038/s41401-018-0084-9
Received: 1 March 2018
Accepted: 19 June 2018
Advance online: 16 July 2018

Abstract

Triptolide (TP) is the main active ingredient of Tripterygium wilfordii Hook.f, which has attracted great interest due to its promising efficacy for autoimmune diseases and tumors. However, severe adverse reactions, especially hepatotoxicity, have restricted its approval in the market. In the present study we explored the role of hepatic natural killer T (NKT) cells in the pathogenesis of TP-induced liver injury in mice. TP (600 μg/kg/day, i.g.) was administered to female mice for 1, 3, or 5 days. We found that administration of TP dose-dependently induced hepatotoxicity, evidenced by the body weight reduction, elevated serum ALT and AST levels, as well as significant histopathological changes in the livers. However, the mice were resistant to the development of TP-induced liver injury when their NKT cells were depleted by injection of anti-NK1.1 mAb (200 μg, i.p.) on days −2 and −1 before TP administration. We further revealed that TP administration activated NKT cells, dominantly releasing Th1 cytokine IFN-γ, recruiting neutrophils and macrophages, and leading to liver damage. After anti-NK1.1 injection, however, the mice mainly secreted Th2 cytokine IL-4 in the livers and exhibited a significantly lower percentage of hepatic infiltrating neutrophils and macrophages upon TP challenge. The activation of NKT cells was associated with the upregulation of Toll-like receptor (TLR) signaling pathway. Collectively, these results demonstrate a novel role of NKT cells contributing to the mechanisms of TP-induced liver injury. More importantly, the regulation of NKT cells may promote effective measures that control drug-induced liver injury.
Keywords: triptolide; drug-induced liver injury; natural killer T cell; Th1/Th2 cytokines; IFN-γ; IL-4; toll-like receptor signaling pathway

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