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

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.

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Acknowledgements

The present study was supported by the National Natural Science Foundation of China (No. 81703626, No. 81773995, No. 81773827, No. 81573514, No. 81673684, No. 81673443, No. 81573690, and No. 81320108029), the Fundamental Research Funds for the Central Universities (2632017PY11), the Natural Science Foundation of Jiangsu Province (BK20151439), and grants from the College Students Innovation Project for the R&D of Novel Drugs (J1310032).

Author contributions

X-zW designed the experiments; X-zW, R-fX, and S-yZ performed the experiments; X-zW, Y-tZ, and L-yZ analyzed and discussed the data; X-zW and Z-zJ wrote the paper. All authors contributed to editing of the paper and scientific discussions.

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Competing interests

The authors declare no competing interests.

Correspondence to Lu-yong Zhang or Zhen-zhou Jiang.

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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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