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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Diclofenac inhibits tumor necrosis factor-alpha-induced nuclear factor-kappaB activation causing synergistic hepatocyte apoptosis.
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Diclofenac inhibits tumor necrosis factor-alpha-induced nuclear factor-kappaB activation causing synergistic hepatocyte apoptosis.

机译：双氯芬酸抑制肿瘤坏死因子-α诱导的核因子-κB活化，引起协同肝细胞凋亡。

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摘要

Drug-induced liver injury (DILI) is an important clinical problem. It involves crosstalk between drug toxicity and the immune system, but the exact mechanism at the cellular hepatocyte level is not well understood. Here we studied the mechanism of crosstalk in hepatocyte apoptosis caused by diclofenac and the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). HepG2 cells were treated with diclofenac followed by TNF-alpha challenge and subsequent evaluation of necrosis and apoptosis. Diclofenac caused a mild apoptosis of HepG2 cells, which was strongly potentiated by TNF-alpha. A focused apoptosis machinery short interference RNA (siRNA) library screen identified that this TNF-alpha-mediated enhancement involved activation of caspase-3 through a caspase-8/Bid/APAF1 pathway. Diclofenac itself induced sustained activation of c-Jun N-terminal kinase (JNK) and inhibition of JNK decreased both diclofenac and diclofenac/TNF-alpha-induced apoptosis. Live cell imaging of GFPp65/RelA showed that diclofenac dampened the TNF-alpha-mediated nuclear factor kappaB (NF-kappaB) translocation oscillation in association with reduced NF-kappaB transcriptional activity. This was associated with inhibition by diclofenac of the TNF-alpha-induced phosphorylation of the inhibitor of NF-kappaB alpha (IkappaBalpha). Finally, inhibition of IkappaB kinase beta (IKKbeta) with BMS-345541 as well as stable lentiviral short hairpin RNA (shRNA)-based knockdown of p65/RelA sensitized hepatocytes towards diclofenac/TNF-alpha-induced cytotoxicity. CONCLUSION: Together, our data suggest a model whereby diclofenac-mediated stress signaling suppresses TNF-alpha-induced survival signaling routes and sensitizes cells to apoptosis.
机译：药物性肝损伤（DILI）是重要的临床问题。它涉及药物毒性和免疫系统之间的串扰，但在细胞肝细胞水平上的确切机制尚不清楚。在这里，我们研究了由双氯芬酸和促炎细胞因子肿瘤坏死因子α（TNF-alpha）引起的肝细胞凋亡中的串扰机制。先用双氯芬酸处理HepG2细胞，然后用TNF-α攻击，然后评估坏死和凋亡。双氯芬酸引起HepG2细胞轻度凋亡，TNF-α强烈增强了它的凋亡。集中的凋亡机制短干扰RNA（siRNA）库筛选确定该TNF-alpha介导的增强涉及通过caspase-8 / Bid / APAF1途径激活caspase-3。双氯芬酸本身诱导c-Jun N末端激酶（JNK）的持续活化，并且JNK的抑制降低了双氯芬酸和双氯芬酸/TNF-α诱导的细胞凋亡。 GFPp65 / RelA的活细胞成像显示，双氯芬酸可抑制TNF-α介导的核因子kappaB（NF-kappaB）易位振荡，并降低NF-kappaB的转录活性。这与双氯芬酸抑制TNF-α诱导的NF-κBα（IkappaBalpha）抑制剂的磷酸化有关。最后，用BMS-345541抑制IkappaB激酶beta（IKKbeta）以及稳定的基于慢病毒短发夹RNA（shRNA）的p65 / RelA致敏肝细胞对双氯芬酸/TNF-α诱导的细胞毒性的抑制作用。结论：在一起，我们的数据提出了一种模型，在该模型中，双氯芬酸介导的应激信号转导抑制了TNF-α诱导的生存信号转导途径并使细胞对凋亡敏感。

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