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

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-? as a potent repressor of HIF-dependent transcription in human intestinal epithelial cells. Analysis of HIF levels revealed that HIF-1?, but not HIF-1?, is selectively repressed by IFN-? in a JAK-dependent manner. Cloning and functional analysis of the HIF-1? promoter identified a prominent region for IFN-?-dependent repression. Further studies revealed that colonic IFN-? and HIF-1? levels were inversely correlated in a murine colitis model. Taken together, these studies demonstrated that intestinal epithelial HIF is attenuated by IFN-? through transcriptional repression of HIF-1?. These observations are relevant to the pathophysiology of colitis (i.e., that loss of HIF signaling during active inflammation may exacerbate disease pathogenesis).

SUBMITTER: Glover LE 

PROVIDER: S-EPMC4040106 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature