Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor
Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor
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DOI：
10.1016/s0016-5085(98)70034-4
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发表时间：
1998-12-01
期刊：
影响因子：
29.4
通讯作者：
Fernández-Checa, JC
中科院分区：
文献类型：
--
作者：
Colell, A;Gargía-Ruiz, C;Fernández-Checa, JC
背景与目的：肿瘤坏死因子（TNF）-α通过线粒体产生氧化应激诱导细胞损伤。本研究的目的是确定乙醇对肝细胞对TNF-α致敏的影响。研究方法：培养的肝细胞从乙醇喂养（乙醇肝细胞）或配对喂养（对照肝细胞）大鼠暴露于TNF-α，氧化应激，基因表达和活力的程度进行了评价，结果：乙醇肝细胞，开发线粒体谷胱甘肽（mGSH）的选择性缺乏，显示出显着的敏感性TNF-α。对TNF-α的易感性表现为坏死而不是凋亡，伴随着过氧化氢的逐渐增加，与细胞存活呈负相关。在乙醇肝细胞中，TNF-α对核因子KB的激活作用显著高于对照肝细胞，这一效应受到了尼古丁诱导的中性粒细胞趋化因子表达的影响。正常肝细胞对TNF-α的敏感性通过用3-羟基-4-戊烯酸耗尽GSH的线粒体池获得，通过S-腺苷-L-甲硫氨酸或GSH-乙酯恢复mGSH防止乙醇肝细胞对TNF-α的敏感性增加。结论：这些结果表明mGSH控制肝细胞对TNF-α的应答的命运。酒精消耗导致的TNF-α消耗放大了TNF-α产生活性氧的能力，损害了线粒体和细胞功能，最终导致细胞死亡。
Background & Aims: Tumor necrosis factor (TNF)-alpha induces cell injury by generating oxidative stress from mitochondria. The purpose of this study was to determine the effect of ethanol on the sensitization of hepatocytes to TNF-alpha. Methods: Cultured hepatocytes from ethanol-fed (ethanol hepatocytes) or pair-fed (control hepatocytes) rats were exposed to TNF-alpha, and the extent of oxidative stress, gene expression, and viability were evaluated, Results: Ethanol hepatocytes, which develop a selective deficiency of mitochondrial glutathione (mGSH), showed marked susceptibility to TNF-alpha. The susceptibility to TNF-alpha, manifested as necrosis rather than apoptosis, was accompanied by a progressive increase in hydrogen peroxide that correlated inversely with cell survival. Nuclear factor KB activation by TNF-alpha was significantly greater in ethanol hepatocytes than in control hepatocytes, an effect paralleled by the expression of cytokine-induced neutrophil chemoattractant. Similar sensitization of normal hepatocytes to TNF-alpha was obtained by depleting the mitochondrial pool of GSH with 3-hydroxyl-4-pentenoate, Restoration of mGSH by S-adenosyl-L-methionine or by GSH-ethyl ester prevented the increased susceptibility of ethanol hepatocytes to TNF-alpha, Conclusions: These results indicate that mGSH controls the fate of hepatocytes in response to TNF-alpha. Its depletion caused by alcohol consumption amplifies the power of TNF-alpha to generate reactive oxygen species, compromising mitochondrial and cellular functions that culminate in cell death.