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

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-? inhibitor, etanercept, was injected intraperitoneally into mice to investigate whether induction of TNF-? by LPS participated in the liver injury induced by TP/LPS co-treatment. Mice and hepatocytes pretreated with TP were stimulated with recombinant TNF-? to assess the function of TNF-? in TP/LPS co-treatment. Additionally, time-dependent NF-?B activation and NF-?B-mediated pro-survival signals were measured in vivo and in vitro. Finally, overexpression of cellular FLICE-inhibitory protein (FLIP), the most potent NF-?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-?, revealing the role of TNF-? in TP/LPS-induced hepatotoxicity. Mechanistic studies revealed that TP inhibited NF-?B dependent pro-survival signals, especially FLIP, induced by LPS/TNF-?. Moreover, overexpression of FLIP alleviated TP/LPS-induced hepatotoxicity in vivo and TP/TNF-?-induced apoptosis in vitro. Mice and hepatocytes treated with TP were sensitive to TNF-?, which was released from LPS-stimulated immune cells. These and other results show that the TP-induced inhibition of NF-?B-dependent transcriptional activity and FLIP production are responsible for liver hypersensitivity.

SUBMITTER: Yuan Z

PROVIDER: S-EPMC7280150 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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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.

Yuan Ziqiao Z Yuan Zihang Z Hasnat Muhammad M Zhang Haoran H Liang Peishi P Sun Lixin L Jiang Zhenzhou Z Zhang Luyong L

Acta pharmaceutica Sinica. B 20200228 5

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 ind ...[more]

PMID: 32528833

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Project description:BackgroundCytoplasmic viral double-stranded RNA (dsRNA) is detected by a class of ubiquitous cytoplasmic RNA helicases, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation antigen-5 (MDA5), which initiate a signaling cascade via their common adaptor called interferon-? (IFN-?) promoter stimulator-1 (IPS-1). This leads to the production of proinflammatory and antiviral cytokines, the type I Interferons, via mainly nuclear factor kappa B (NF-?B) and interferon response factor-3 (IRF3) transcription factors. Fas-associated death domain (FADD) protein, receptor-interacting protein (RIP1), caspase-8 and tumor necrosis factor receptor (TNFR)-associated death domain (TRADD) protein, all traditionally associated with death receptor signaling, are also involved in RIG-I/MDA5 signaling pathway. We previously showed that FLIP (Flice-like inhibitory protein), also designated as cflar (CASP8 and FADD-like apoptosis regulator), negatively regulates lipopolysaccharide (LPS)-induced toll-like receptor 4 (TLR4) signaling in endothelial cells and mouse embryonic fibroblasts (MEFs) and protected against TLR4-mediated apoptosis.ResultsIn this study, we investigated the role of FLIP in cellular response to cytoplasmic polyinosinic:polycytidylic acid, poly(I:C), a synthetic analog of dsRNA. Consistent with the previously described role of FADD in RIG-I/MDA5-mediated apoptosis, we found that FLIP-/- MEFs were more susceptible to killing by cytoplasmic poly(I:C). However, FLIP-/- MEFs also exhibited markedly increased expression of NF-?B-and IRF3- dependent genes in response to cytoplasmic poly(I:C). Importantly, reconstitution of FLIP in FLIP-/-MEFs reversed the hyper-activation of IRF3- and NF-?B-mediated gene expression. Further, we found that caspase-8 catalytic activity was not required for cytoplasmic poly(I:C)-mediated NF-?B and IRF3 signaling.ConclusionsThese results provide evidence for a crucial dual role for FLIP in antiviral responses to cytoplasmic dsRNA: it protects from cytoplasmic dsRNA-mediated cell death while down-regulating IRF3-and NF-?B-mediated gene expression. Since the pathogenesis of several viral infections involves a heightened and dysregulated cytokine response, a possible therapy could involve modulating FLIP levels.

Dataset Information

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

Publications

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

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