ToxSci Advance Access originally published online on March 30, 2006
Toxicological Sciences 2006 91(2):643-650; doi:10.1093/toxsci/kfj175
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Mitochondrial Thioredoxin-2 Has a Key Role in Determining Tumor Necrosis Factor-
–Induced Reactive Oxygen Species Generation, NF-
B Activation, and Apoptosis
* Division of Pulmonary, Asthma, Cystic Fibrosis and Sleep, Department of Pediatrics and Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia 30322
Received January 12, 2006; accepted March 1, 2006
Tumor necrosis factor-
(TNF-) is a cytokine that is involved in numerous pathologies, in part through stimulation of the mitochondrial production of reactive oxygen species (ROS). Previous studies show that in addition to mitochondrial superoxide dismutase- and glutathione-dependent systems, mitochondria also contain thioredoxin-2 (Trx2), an antioxidant protein that can detoxify ROS. The purpose of this study was to determine whether Trx2 protects against oxidative damage triggered by TNF-. After a 30-min treatment in HeLa cells, TNF- (5–40 ng/ml) oxidized Trx2 but not cytoplasmic Trx1. Preferential, significant Trx2 oxidation occurred within 10 min of TNF- treatment. Moreover, overexpression of Trx2, but not Trx1, decreased TNF-–induced ROS generation, suggesting mitochondrial compartmentation of ROS production and subsequent specific detoxification by Trx2, not Trx1. Overexpression of Trx2 or the active-site mutant C93S Trx2 was used to evaluate their downstream effects following TNF- stimulation. Results showed that nuclear translocation of NF-
B was inhibited with Trx2 overexpression but not with the dominant negative active-site mutant C93S Trx2. Moreover, when cotransfected with a NF-B-luciferase reporter and then treated with TNF-, NF-B activity was significantly attenuated with Trx2 overexpression but not with C93S Trx2 expression. Trx2 overexpression, but not C93S Trx2, significantly inhibited TNF-–induced apoptosis as measured by terminal dUTP nick-end labeling assay. These findings support the interpretation that mitochondrial-generated ROS is a principal component in TNF-–induced effects and that Trx2 blocks TNF-–induced ROS generation and downstream NF-B activation and apoptosis.
Key Words: NF-B; apoptosis; oxidative damage; ROS generation; thioredoxin; TNF-.
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