Hepatocellular apoptosis is mediated by TNFα-dependent Fas/FasLigand cytotoxicity in a murine model of acute liver failure
Hepatocellular apoptosis is mediated by TNFα-dependent Fas/FasLigand cytotoxicity in a murine model of acute liver failure
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DOI：
10.1007/s10495-008-0269-7
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发表时间：
2008-12-01
期刊：
影响因子：
7.2
通讯作者：
Vollmar, Brigitte
中科院分区：
文献类型：
--
作者：
Kuhla, Angela;Eipel, Christian;Vollmar, Brigitte
越来越多的证据表明，肝细胞对肝脏疾病的积极贡献强烈依赖于局部细胞因子环境。体外研究表明，TNF α可以增强肝细胞FasL介导的细胞毒性。在这里，我们证明TNF α诱导的细胞凋亡与Fas和FasL上调有关，FasL中和抗体阻止TNF α诱导的细胞凋亡。在TNF α驱动的急性肝衰竭模型中，我们进一步在体内研究了Fas/FasL通路与肝细胞凋亡的相关性。半乳糖胺/脂多糖（Gal/LPS）暴露的Fas野生型小鼠肝脏高度表达Fas和FasL，并显示明显的肝细胞凋亡，几乎完全被可溶性TNF α受体阻断；这在Gal/ lps暴露的Fas淋巴细胞增殖突变小鼠中也几乎不存在。我们的数据为TNF α和Fas/FasL介导肝细胞凋亡之间的直接联系提供了证据。邻近肝细胞fasl - fasl相互作用导致的自相残杀可能是急性肝衰竭的积极诱因。
There is increasing evidence that the active contribution of hepatocytes to liver disease is strongly dependent on local cytokine environment. It has been shown in vitro that TNF alpha can enhance hepatocyte FasLigand (FasL)-mediated cytotoxicity. Here, we demonstrate that TNF alpha-induced apoptosis was associated with Fas and FasL upregulation and that a FasL-neutralizing antibody prevented TNF alpha-induced apoptosis. We further examined in vivo the relevance of the Fas/FasL pathway to hepatocellular apoptosis in a TNF alpha-driven model of acute liver failure. Livers of galactosamine/lipopolysaccharide (Gal/LPS)-exposed Fas wild-type mice highly expressed both Fas and FasL and revealed marked hepatocellular apoptosis that was almost completely blocked by soluble TNF alpha-receptor; this was also almost absent in Gal/LPS-exposed Fas lymphoproliferation mutant mice. Our data provide evidence for a direct link between TNF alpha and Fas/FasL in mediating hepatocyte apoptosis. Fratricidal death by Fas-FasL interactions of neighbouring hepatocytes may actively contribute to acute liver failure.