TNF-α-induced cell death in ethanol-exposed cells depends on p38 MAPK signaling but is independent of bid and caspase-8
TNF-α-induced cell death in ethanol-exposed cells depends on p38 MAPK signaling but is independent of bid and caspase-8
复制标题
DOI：
10.1152/ajpgi.00442.2002
复制
发表时间：
2003-09-01
影响因子：
4.5
通讯作者：
Hoek, JB
中科院分区：
文献类型：
--
作者：
Pastorino, JG;Shulga, N;Hoek, JB
酒精性肝病与坏死和凋亡肝实质细胞数量增加有关。这种损伤的一部分由TNF-α介导。乙醇暴露使细胞对TNF-α的细胞毒性作用敏感。这可能是由于，在一定程度上，在乙醇暴露的细胞中的线粒体诱导线粒体通透性转换（MPT）的各种代理，包括促凋亡蛋白Bax的倾向增加。这一观点得到了以下观察结果的支持：在乙醇暴露的细胞中，TNF-α诱导的细胞死亡增加依赖于MPT的发展。在本研究中，我们阐明了乙醇暴露增强TNF-α诱导MPT和产生的细胞毒性的途径。具体而言，乙醇暴露的细胞在TNF-α处理期间显示半胱天冬酶-8和Bid非依赖性细胞杀伤。此外，乙醇增强的途径依赖于p38 MAPK信号传导，其导致半胱天冬酶-3活化、线粒体去极化、细胞色素c在胞质溶胶中的积累以及Bax向线粒体的易位。此外，乙醇暴露的细胞显示出TNF-α诱导的Akt活化和细胞死亡磷酸化的Bcl-2拮抗剂的钝化，这可能部分地解释了线粒体对TNF-α介导的损伤的敏感性增加。
Alcoholic liver disease is associated with an increase in the number of necrotic and apoptotic liver parenchymal cells. Part of this injury is mediated by TNF-alpha. Ethanol exposure sensitizes cells to the cytotoxic effects of TNF-alpha. This may be due, in part, to the increased propensity of the mitochondria in ethanol-exposed cells to induction of mitochondrial permeability transition (MPT) by various agents, including the proapoptotic protein Bax. This idea is supported by the observation that increased cell death induced by TNF-alpha in ethanol-exposed cells was dependent on development of the MPT. In the present study, we elucidate the pathways through which ethanol exposure enhances TNF-alpha induction of the MPT and the resulting cytotoxicity. Specifically, ethanol-exposed cells display caspase-8- and Bid-independent cell killing during TNF-alpha treatment. Moreover, the ethanol-enhanced pathway is dependent on p38 MAPK signaling, which brings about caspase-3 activation, mitochondrial depolarization, accumulation of cytochrome c in the cytosol, and the translocation of Bax to the mitochondria. Additionally, ethanol-exposed cells display a blunting of TNF-alpha-induced Akt activation and Bcl-2 antagonist of cell death phosphorylation that may account, in part, for the increased sensitivity of the mitochondria to Bax-mediated damage.