title: IFN-γ attenuates hypoxia-inducible factor (HIF) activity in intestinal epithelial cells through transcriptional repression of HIF-1β.
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).
authors.affiliation: Mucosal Inflammation Program, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Glover
authors.forename: Karina
authors.initials: K
authors.lastname: Irizarry
authors.forename: Melanie
authors.initials: M
authors.lastname: Scully
authors.forename: Eric L
authors.initials: EL
authors.lastname: Campbell
authors.forename: Brittelle E
authors.initials: BE
authors.lastname: Bowers
authors.forename: Carol M
authors.initials: CM
authors.lastname: Aherne
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kominsky
authors.forename: Christopher F
authors.initials: CF
authors.lastname: MacManus
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003092:Colitis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology*; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011393:Procollagen-Proline Dioxygenase / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D018836:Inflammation Mediators; D012097:Repressor Proteins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D007371:Interferon-gamma; D016264:Dextran Sulfate; D011393:Procollagen-Proline Dioxygenase