摘要
Previously,we proposed a new perspective of triptolide(TP)-associated hepatotoxicity:liver hypersensitivity upon lipopolysaccharide(LPS)stimulation.However,the mechanisms for TP/LPSinduced 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.TSF-αinhibitor,etanercept,was injected intraperitoneally into mice to investigate whether induction of TNF-αby LPS participated in the liver injury induced by TP/LPS co-treatment.Mice and hepatocytes pretreated with TP were stimulated with recombinant TNF-αto assess the function of TNF-αin TP/LPS co-treatment.Additionally,time-dependent MF-κB activation and NF-κB-mediated pro-survival signals were measured in vivo and in vitro.Finally,overexpression of cellular FLICEinhibitory protein(FLIP),the most potent NF-κB-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-αin TP/LPS-induced hepatotoxicity.Mechanistic studies revealed that TP inhibited NF-κB 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-κB-dependent transcriptional activity and FLIP production are responsible for liver hypersensitivity.
基金
supported by the National Natural Science Foundation of China(81973562,81773995,81773827,81320108029,81573690,81573514,and 81673684)
the National“Major Scientific and Technological Special Project for Significant New Drugs”project(2015ZX09501004-002-004,China)
Specific Fund for Public Interest Research of Traditional Chinese Medicine,Ministry of Finance(201507004-002,China)
"Double First-Class"University project(CPU2018GY33,China)
作者简介
Corresponding author:Zhenzhou Jiang,E-mail addresses:beaglejiang@cpu.edu.cn;Corresponding author:Luyong Zhang,lyzhangchina@hotmail.com
