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A new perspective of triptolide-associated hepatotoxicity: the relevance of NF- κ B and NF- κ B-mediated cellular FLICE-inhibitory protein.
- Source :
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Acta pharmaceutica Sinica. B [Acta Pharm Sin B] 2020 May; Vol. 10 (5), pp. 861-877. Date of Electronic Publication: 2020 Feb 28. - Publication Year :
- 2020
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Abstract
- 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.<br />Competing Interests: The authors declare no conflicts of interest.<br /> (© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)
Details
- Language :
- English
- ISSN :
- 2211-3835
- Volume :
- 10
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Acta pharmaceutica Sinica. B
- Publication Type :
- Academic Journal
- Accession number :
- 32528833
- Full Text :
- https://doi.org/10.1016/j.apsb.2020.02.009