Overexpression of thioredoxin reductase 1 regulates NF-kappa B activation.
Thioredoxin reductase (TrxR) is a flavoprotein that contains a C-terminal penultimate selenocysteine (Sec) and has an ability to reduce thioredoxin (Trx), which regulates the activity of NF-kappa B. To date, three TrxR isozymes, TrxR1, TrxR2, and TrxR3, have been identified. In the present study, we found that among these isozymes only TrxR1 was induced by tumor necrosis factor-alpha (TNF alpha) in vascular endothelial cells. Furthermore, the overexpression of TrxR1 enhanced TNF alpha-induced DNA-binding activity of NF-kappa B and NF-kappa B-dependent gene expression. The catalytic Sec residue of TrxR1, which is essential for reducing Trx, was required for this NF-kappa B activation, and aurothiomalate, an inhibitor of TrxR, suppressed TNF alpha-induced activation of NF-kappa B and the expression of NF-kappa B-targeted proinflammatory genes such as E-selectin and cyclooxygenase-2. These results suggest that TrxR1 may act as a positive regulator of NF-kappa B and may play an important role in the cellular inflammatory response.
Department of Public Health and Molecular Toxicology, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Atsuko
A
Sakurai
Kouji
K
Yuasa
Yasuko
Y
Shoji
Seiichiro
S
Himeno
Masafumi
M
Tsujimoto
Manabu
M
Kunimoto
Nobumasa
N
Imura
Shuntaro
S
Hara
D000818:Animals; D018501:Antirheumatic Agents / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006052:Gold Sodium Thiomalate / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D054481:Thioredoxin Reductase 1; D013880:Thioredoxin-Disulfide Reductase / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018501:Antirheumatic Agents; D007527:Isoenzymes; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D006052:Gold Sodium Thiomalate; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D013880:Thioredoxin-Disulfide Reductase; C516125:Txnrd1 protein, mouse