Abstract
Hypoxia and inflammation occur coincidentally in mucosal diseases such as inflammatory bowel disease (IBD). Hypoxia inducible factor (HIF) has been implicated as a regulatory pathway under such conditions. HIF is a transcription factor critical to adaptation to low oxygen states and several studies have indicated that intestinal epithelial HIF provides protection in murine models of colitis. We therefore hypothesized that inflammation‐relevant mediators may influence intestinal epithelial expression and function of HIF.Guided by an initial screen of relevant inflammatory mediators, we analyzed the influence of IFN‐γ on HIF expression and transcriptional activity in intestinal epithelial cells. Epithelial exposure to IFN‐γ resulted in a concentration‐dependent repression of HIF activity (p<0.025) that was reversible in the presence of transcriptional inhibition. A real‐time PCR screen revealed prominent inhibition of HIF‐1β, but not HIF‐1α expression, by IFN‐γ. Analysis of the human HIF‐1β promoter confirmed the inhibitory influence of IFN‐γ on HIF‐1β activity. Taken together, these studies demonstrate that HIF activity and expression in intestinal epithelial cells is specifically repressed by IFN‐γ through a mechanism involving transcriptional repression of the HIF‐1β promoter. These observations may be relevant to the pathophysiology of colitis. (NIH, USA)
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