Journal
CYTOKINE
Volume 46, Issue 3, Pages 359-369Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.cyto.2009.03.010
Keywords
ROS; Ref-1; TNF-alpha; IL-8; AGS cell
Funding
- National Institutes of Health [R01 DK61769, R01 ES 08457, R01 DK51677, DK67629]
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TNF-alpha contributes to oxidative stress via induction of reactive oxygen species (ROS) and pro-inflammatory cytokines. The molecular basis of this is not well understood but it is partly mediated through the inducible expression of IL-8. As redox factor-1 (Ref-1), is an important mediator of redox-regulated gene expression we investigated whether ROS and Ref-1 modulate TNF-alpha-induced IL-8 expression in human gastric epithelial cells. We found that TNF-alpha treatment of AGS cells enhanced nuclear expression of Ref-1 and potently induced IL-8 expression. Overexpression of Ref-1 enhanced IL-8 gene transcription at baseline and after TNF-alpha treatment whereas Ref-1 suppression and antioxidant treatment inhibited TNF-alpha-stimulated IL-8 expression. TNF-alpha-mediated enhancement of other pro-inflammatory chemokines like MIP-3 alpha and Gro-alpha was also regulated by Ref-1. Although TNF-alpha increased DNA binding activity of Ref-1-regulated transcription factors, AP-1 and NF-kappa B, to the IL-8 promoter, promoter activity was mainly mediated by NF-kappa B binding. Silencing of Ref-I in AGS cells inhibited basal and TNF-alpha-induced AP-1 and NF-kappa B DNA binding activity, but not their nuclear accumulation. Collectively, we provide the first mechanistic evidence of Ref-I involvement in TNF-alpha-mediated, redox-sensitive induction of IL-8 and other chemokines in human gastric mucosa. This has implications for understanding the pathogenesis of gastrointestinal inflammatory disorders. (C) 2009 Published by Elsevier Ltd.
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