ToxSci Advance Access published online on March 30, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj175
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1 Division of Pulmonary, Asthma, Cystic Fibrosis and Sleep, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322
* To whom correspondence should be addressed. Tumor necrosis factor-
Received January 12, 2006
Accepted March 1, 2006
Systems Toxicology
Mitochondrial Thioredoxin-2 has a Key Role in Determining Tumor Necrosis Factor-
Jason M. Hansen 1 *,
Hong Zhang 2,
and
Dean P. Jones 2
-Induced ROS Generation, NF-
B Activation and Apoptosis
2 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, Emory University, Atlanta, GA 30322
Jason M. Hansen, E-mail: jhansen{at}emory.edu
Abstract 
(TNF) is a cytokine that is involved in numerous pathologies, in part through stimulation of 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 thioredoxin-1 (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. To determine whether Trx2 inhibited processes downstream of mitochondrial ROS, effects of overexpression of Trx2 and the active-site mutant (C93S Trx2) on TNF-dependent NF-
B activation and apoptosis. 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 co-transfected with a NF-B-Luciferase reporter and then treated with TNF, NF-B activity was significantly attenuated with Trx2 overexpression but not by C93S Trx2 expression. Trx2 overexpression, but not C93S Trx2, significantly inhibited TNF-induced apoptosis as measured by TUNEL 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.
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