Role of oxidants in NF-κB activation and TNF-α gene transcription induced by hypoxia and endotoxin

被引:438
作者
Chandel, NS [1 ]
Trzyna, WC [1 ]
McClintock, DS [1 ]
Schumacker, PT [1 ]
机构
[1] Northwestern Univ, Dept Med, Div Pulm & Crit Care, Chicago, IL 60611 USA
关键词
D O I
10.4049/jimmunol.165.2.1013
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The transcription factor NF-kappa B stimulates the transcription of proinflammatory cytokines including TNF-alpha, LPS (endotoxin) and hypoxia both induce NF-kappa B activation and TNF-alpha gene transcription. Furthermore, hypoxia augments LPS induction of TNF-alpha mRNA. Previous reports have indicated that antioxidants abolish NF-kappa B activation in response to LPS or hypoxia, which suggests that reactive oxygen species (ROS) are involved in NF-kappa B activation. This study tested whether mitochondrial ROS are required for both NF-kappa B activation and the increase in TNF-alpha mRNA levels during hypoxia and LPS, Our results indicate that hypoxia (1.5% O-2) stimulates NF-kappa B and TNF-alpha gene transcription and increases ROS generation as measured by the oxidant sensitive dye 2',7'-dichlorofluorescein diacetate in murine macrophage J774.1 cells. The antioxidants N-acetylcysteine and pyrrolidinedithiocarbamic acid abolished the hypoxic activation of NF-kappa B, TNF-alpha gene transcription, and increases in ROS levels. Rotenone, an inhibitor of mitochondrial complex I, abolished the increase in ROS signal, the activation of NF-kappa B, and TNF-alpha gene transcription during hypoxia. LPS stimulated NF-kappa B and TNF-alpha gene transcription but not ROS generation in J774.1 cells. Rotenone, pyrrolidinedithiocarbamic acid, and N-acetylcysteine had no effect on the LPS stimulation of NF-kappa B and TNF-alpha gene transcription, indicating that LPS activates NF-kappa B and TNF-alpha gene transcription through a ROS-independent mechanism. These results indicate that mitochondrial ROS are required for the hypoxic activation of NF-kappa B and TNF-LU gene transcription, but not for the LPS activation of NF-kappa B.
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收藏
页码:1013 / 1021
页数:9
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