Hypoxia‐Inducible Factor‐2α Promotes Intestinal Inflammation Through Induction of Epithelial TNF‐α

Abstract

Background & AimsHypoxia can induce a robust inflammatory process termed “hypoxic inflammation”, which is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia‐inducible factor (HIF)‐1α and HIF‐2α, both of which are highly induced in IBD. HIF‐1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF‐2α has not been assessed in hypoxic inflammation and IBD. We hypothesize that HIF‐2α promotes hypoxic inflammation during the progression of IBD.MethodsThe role of HIF‐2α in colitis was assessed in dextran sulfate sodium and citrobacter‐induced colitis mouse models with intestine‐specific gain‐ and loss‐of‐function of HIF‐2α.ResultsActivation of HIF‐2α potentiated colonic inflammation, whereas disruption of HIF‐2α attenuated inflammation in these mouse models of colitis. Further mechanistic analysis showed that HIF‐2α is a master regulator of epithelial derived pro‐inflammatory meditators and directly regulates epithelial tumor necrosis factor (TNF)‐α. In silico analysis predicted and luciferase reporter assay verified that the transcription factor MAZ could bind to TNF‐α promoter and potentiate HIF‐2α mediated TNF‐α induction.ConclusionsThese data demonstrate that HIF‐2α is a critical transcription factor essential in intestinal inflammatory response.Funding:National Institutes of Health (grant CA148828 to Y.M.S.); The University of Michigan Gastrointestinal Peptide Center; Jeffrey A.Colby Colon Cancer Research and the Tom Liu Memorial Funds of the University of Michigan Comprehensive Cancer Center.