PMID- 21526215
OWN - NLM
STAT- MEDLINE
DCOM- 20110816
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 4
DP  - 2011 Apr 15
TI  - Increased inflammatory signaling and lethality of influenza H1N1 by nuclear 
      thioredoxin-1.
PG  - e18918
LID - 10.1371/journal.pone.0018918 [doi]
LID - e18918
AB  - 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-kappaB 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-kappaB activation, increased TNF-alpha 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. CONCLUSION/SIGNIFICANCE: Increased Trx1 in 
      cell nuclei can increase severity of disease responses by potentiation of 
      redox-sensitive transcription factor activation.
FAU - Go, Young-Mi
AU  - Go YM
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Department of 
      Medicine, Emory University, Atlanta, Georgia, United States of America.
FAU - Kang, Sang-Moo
AU  - Kang SM
FAU - Roede, James R
AU  - Roede JR
FAU - Orr, Michael
AU  - Orr M
FAU - Jones, Dean P
AU  - Jones DP
LA  - eng
GR  - R01 ES009047/ES/NIEHS NIH HHS/United States
GR  - R01 ES011195/ES/NIEHS NIH HHS/United States
GR  - ES011195/ES/NIEHS NIH HHS/United States
GR  - ES009047/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110415
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antioxidants)
RN  - 0 (Cytokines)
RN  - 0 (Glucocorticoids)
RN  - 0 (NF-kappa B)
RN  - 0 (Nuclear Localization Signals)
RN  - 0 (RNA, Messenger)
RN  - 52500-60-4 (Thioredoxins)
RN  - ULW86O013H (Glutathione Disulfide)
SB  - IM
MH  - Animals
MH  - Antioxidants/metabolism
MH  - Apoptosis/drug effects
MH  - Cell Nucleus/drug effects/*metabolism
MH  - Cytokines/metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Glucocorticoids/pharmacology
MH  - Glutathione Disulfide/blood
MH  - Humans
MH  - Inflammation/*complications/pathology
MH  - Influenza A Virus, H1N1 Subtype/drug effects/*physiology
MH  - Influenza, Human/*complications/metabolism/mortality/*virology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - NF-kappa B/metabolism
MH  - Nuclear Localization Signals/metabolism
MH  - Orthomyxoviridae Infections/complications/mortality/pathology/virology
MH  - Oxidation-Reduction/drug effects
MH  - Protein Transport/drug effects
MH  - RNA, Messenger/genetics/metabolism
MH  - *Signal Transduction/drug effects
MH  - Thioredoxins/genetics/*metabolism
MH  - Weight Loss
PMC - PMC3078150
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/04/29 06:00
MHDA- 2011/08/17 06:00
PMCR- 2011/04/15
CRDT- 2011/04/29 06:00
PHST- 2010/10/17 00:00 [received]
PHST- 2011/03/25 00:00 [accepted]
PHST- 2011/04/29 06:00 [entrez]
PHST- 2011/04/29 06:00 [pubmed]
PHST- 2011/08/17 06:00 [medline]
PHST- 2011/04/15 00:00 [pmc-release]
AID - PONE-D-10-03510 [pii]
AID - 10.1371/journal.pone.0018918 [doi]
PST - epublish
SO  - PLoS One. 2011 Apr 15;6(4):e18918. doi: 10.1371/journal.pone.0018918.