IFN-γ attenuates hypoxia-inducible factor (HIF) activity in intestinal epithelial cells through transcriptional repression of HIF-1β

Louise E. Glover, Karina Irizarry, Melanie Scully, Eric L. Campbell, Brittelle E. Bowers, Carol M. Aherne, Douglas J. Kominsky, Christopher F. MacManus, Sean P. Colgan

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Abstract

Numerous studies have revealed that hypoxia and inflammation occur coincidentally in mucosal disorders, such as inflammatory bowel disease. During inflammation, epithelial-expressed hypoxia-inducible factor (HIF) serves an endogenously protective function. In this study, we sought to explore how mucosal immune responses influence HIF-dependent end points. Guided by a screen of relevant inflammatory mediators, we identified IFN-γ as a potent repressor of HIF-dependent transcription in human intestinal epithelial cells. Analysis of HIF levels revealed that HIF-1β, but not HIF-1α, is selectively repressed by IFN-γ in a JAK-dependent manner. Cloning and functional analysis of the HIF-1β promoter identified a prominent region for IFN-γ-dependent repression. Further studies revealed that colonic IFN-γ and HIF-1β levels were inversely correlated in a murine colitis model. Taken together, these studies demonstrated that intestinal epithelial HIF is attenuated by IFN-γ through transcriptional repression of HIF-1β. These observations are relevant to the pathophysiology of colitis (i.e., that loss of HIF signaling during active inflammation may exacerbate disease pathogenesis).

Original languageEnglish
Pages (from-to)1790-1798
Number of pages9
JournalJournal of Immunology
Volume186
Issue number3
DOIs
Publication statusPublished - 01 Feb 2011
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Glover, L. E., Irizarry, K., Scully, M., Campbell, E. L., Bowers, B. E., Aherne, C. M., Kominsky, D. J., MacManus, C. F., & Colgan, S. P. (2011). IFN-γ attenuates hypoxia-inducible factor (HIF) activity in intestinal epithelial cells through transcriptional repression of HIF-1β. Journal of Immunology, 186(3), 1790-1798. https://doi.org/10.4049/jimmunol.1001442