A new perspective of triptolide-associated hepatotoxicity: the relevance of NF- κ B and NF- κ B-mediated cellular FLICE-inhibitory protein.

Previously, we proposed a new perspective of triptolide (TP)-associated hepatotoxicity: liver hypersensitivity upon lipopolysaccharide (LPS) stimulation. However, the mechanisms for TP/LPS-induced hepatotoxicity remained elusive. The present study aimed to clarify the role of LPS in TP/LPS-induced hepatotoxicity and the mechanism by which TP induces liver hypersensitivity upon LPS stimulation. TNF- α inhibitor, etanercept, was injected intraperitoneally into mice to investigate whether induction of TNF- α by LPS participated in the liver injury induced by TP/LPS co-treatment. Mice and hepatocytes pretreated with TP were stimulated with recombinant TNF- α to assess the function of TNF- α in TP/LPS co-treatment. Additionally, time-dependent NF- κ B activation and NF- κ B-mediated pro-survival signals were measured in vivo and in vitro . Finally, overexpression of cellular FLICE-inhibitory protein (FLIP), the most potent NF- κ B-mediated pro-survival protein, was measured in vivo and in vitro to assess its function in TP/LPS-induced hepatotoxicity. Etanercept counteracted the toxic reactions induced by TP/LPS. TP-treatment sensitized mice and hepatocytes to TNF- α , revealing the role of TNF- α in TP/LPS-induced hepatotoxicity. Mechanistic studies revealed that TP inhibited NF- κ B dependent pro-survival signals, especially FLIP, induced by LPS/TNF- α . Moreover, overexpression of FLIP alleviated TP/LPS-induced hepatotoxicity in vivo and TP/TNF- α -induced apoptosis in vitro . Mice and hepatocytes treated with TP were sensitive to TNF- α , which was released from LPS-stimulated immune cells. These and other results show that the TP-induced inhibition of NF- κ B-dependent transcriptional activity and FLIP production are responsible for liver hypersensitivity.
Competing Interests: The authors declare no conflicts of interest.
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