title: Increased inflammatory signaling and lethality of influenza H1N1 by nuclear thioredoxin-1.
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.
  
  
  RESULTS
  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 (E(h)GSSG) 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.
  
  
  CONCLUSIONS
  Increased Trx1 in cell nuclei can increase severity of disease responses by potentiation of redox-sensitive transcription factor activation.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Go
authors.forename: Sang-Moo
authors.initials: SM
authors.lastname: Kang
authors.forename: James R
authors.initials: JR
authors.lastname: Roede
authors.forename: Michael
authors.initials: M
authors.lastname: Orr
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D019803:Glutathione Disulfide / Q000097:blood; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000473:pathology; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000502:physiology*; D007251:Influenza, Human / Q000150:complications* / Q000378:metabolism / Q000401:mortality / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000401:mortality / Q000473:pathology / Q000821:virology; D010084:Oxidation-Reduction / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D015431:Weight Loss
chemical_list: D000975:Antioxidants; D016207:Cytokines; D005938:Glucocorticoids; D016328:NF-kappa B; D019913:Nuclear Localization Signals; D012333:RNA, Messenger; D013879:Thioredoxins; D019803:Glutathione Disulfide