Activation of ASK-1 and downstream MAP kinases in cytochrome P4502E1 potentiated tumor necrosis factor alpha liver injury.
Activation of ASK-1 and downstream MAP kinases in cytochrome P4502E1 potentiated tumor necrosis factor alpha liver injury.
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DOI：
10.1016/j.freeradbiomed.2010.04.021
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发表时间：
2010-08-01
影响因子：
7.4
通讯作者：
Cederbaum, Arthur
中科院分区：
文献类型：
--
作者：
Wu, Defeng;Cederbaum, Arthur
Cytochrome P4502E1 (CYP2E1) potentiated TNFα-toxicity by a mechanism involving increased oxidative stress and activation of JNK and p38 MAPKs. The current study evaluated what are the upstream mediators of this MAPK activation with a special focus on studying whether Apoptosis Signal Regulating Kinase-1 (ASK-1) is activated in the CYP2E1-TNFα hepatotoxic model. Wild type and CYP2E1−/− mice were treated with pyrazole (PY) for three days to induce CYP2E1 and challenged with TNFα on day three. Liver injury occurred between 8–12h after TNFα addition only to the wild type PY-treated mice. Oxidative stress was elevated in the PY mice at 4h, a time prior to the liver injury. ASK-1 was dissociated from the thioredoxin-ASK1 complex, and was activated at 4h after addition of TNFα to PY mice. This was followed by activation of MKK3/MKK6 and MKK4/MKK7 at 4–8 or 12h and then JNK/p38 MAPK at 8 to 12h. MAPK phosphatase-1 was decreased 12 to 24h after TNFα addition. This may promote a sustained activation of JNK. Bax was elevated while Bcl-2 and cFLIPS/L were lowered at 4h after addition of TNFα. These changes were followed by increases in caspase 8 and 3 activities and apoptosis. None of the above changes were found when TNFα was added to PY-treated CYP2E1−/− mice. These studies show that TNFα increases oxidative stress in mice with elevated CYP2E1 with subsequent activation of ASK-1 via a mechanism involving thioredoxin/ASK-1 dissociation, followed by activation of downstream MAPKK and MAPK. We speculate that similar interactions between CYP2E1 and TNFα may be important for alcohol-induced liver injury.
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