Increased Inflammatory Signaling and Lethality of Influenza H1N1 by Nuclear Thioredoxin-1

• Type of Material: Article
• Authors: Young-Mi Kanggo, Emory University; Sang-Moo Kang, Emory University; James R. Roede, Emory University; Michael Orr, Emory University; Dean P Jones, Emory University
• Language: English
• Date: 2011-04-15
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2011 Go et al.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0018918
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 6
• Issue: 4
• Start Page: e18918
• End Page: e18918
• Grant/Funding Information: This work was supported by the National Institute of Environmental Health Sciences Grants ES011195 and ES009047. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Research Categories: Health Sciences, Immunology; Biology, Microbiology

Abstract

Background Cell 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 Findings Transgenic 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/Significance Increased Trx1 in cell nuclei can increase severity of disease responses by potentiation of redox-sensitive transcription factor activation.