Abstract
BackgroundCell culture studies show that the antioxidant thiol protein, thioredoxin-1 (Trx1), translocates to cell nuclei during stress, facilitates DNA binding of transcription factors NF-κB and glucocorticoid receptor (GR) and potentiates signaling in immune cells. Excessive proinflammatory signaling in vivo contributes to immune hyper-responsiveness and disease severity, but no studies have addressed whether nuclear Trx1 mediates such responses.Methodology/Principal FindingsTransgenic mice (Tg) expressing human Trx1 (hTrx1) with added nuclear localization signal (NLS) showed broad tissue expression and nuclear localization. The role of nuclear Trx1 in inflammatory signaling was examined in Tg and wild-type (WT) mice following infection with influenza (H1N1) virus. Results showed that Tg mice had earlier and more extensive NF-κB activation, increased TNF-α and IL-6 expression, greater weight loss, slower recovery and increased mortality compared to WT. Decreased plasma glutathione (GSH) and oxidized plasma GSH/GSSG redox potential (EhGSSG) following infection in Tg mice showed that the increased nuclear thiol antioxidant caused a paradoxical downstream oxidative stress. An independent test of this nuclear reductive stress showed that glucocorticoid-induced thymocyte apoptosis was increased by NLS-Trx1.Conclusion/SignificanceIncreased Trx1 in cell nuclei can increase severity of disease responses by potentiation of redox-sensitive transcription factor activation.
Highlights
Thioredoxin-1 (Trx-1) and glutathione (GSH) are central thiol redox systems in cell nuclei and cytoplasm but are differentially regulated in these compartments
This translocation is critical to function of transcription factors that contain a regulatory cysteine in the DNA binding region, including nuclear factor-kB (NF-kB) [4,5,6], glucocorticoid receptor (GR) [7,8], activator protein-1 [9,10,11], nuclear factor-like 2 (Nrf-2) [12,13], Hypoxia-inducible factor 1 alpha (HIF-1a) [14] and p53 [15,16]
Characterization of the abundance and localization of the NLShTrx1 transgene product was facilitated by inclusion of the c-Myc epitope, which allowed discrimination from the endogenous mouse Trx1
Summary
Thioredoxin-1 (Trx-1) and glutathione (GSH) are central thiol redox systems in cell nuclei and cytoplasm but are differentially regulated in these compartments. Little is known about the adaptive mechanisms for the nuclear GSH system, the function of the nuclear Trx system is enhanced by translocation of Trx from cytoplasm to nuclei This translocation is critical to function of transcription factors that contain a regulatory cysteine in the DNA binding region, including nuclear factor-kB (NF-kB) [4,5,6], glucocorticoid receptor (GR) [7,8], activator protein-1 [9,10,11], nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) [12,13], Hypoxia-inducible factor 1 alpha (HIF-1a) [14] and p53 [15,16]. Excessive proinflammatory signaling in vivo contributes to immune hyper-responsiveness and disease severity, but no studies have addressed whether nuclear Trx mediates such responses
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