Premium
The role of hypoxia‐inducible factor‐2[alpha] in regulating colon inflammation
Author(s) -
Shah Yatrik M,
Taylor Matthew
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1123.2
Subject(s) - hypoxia inducible factors , intestinal epithelium , inflammation , pathogenesis , transcription factor , colitis , biology , hypoxia (environmental) , barrier function , intestinal mucosa , hif1a , immunology , cancer research , epithelium , microbiology and biotechnology , gene , medicine , chemistry , angiogenesis , genetics , organic chemistry , oxygen
Dramatic decreases in cellular oxygen levels have been observed during the pathogenesis of colitis, however the functional consequences to either observation are currently unclear. Regulation of hypoxia‐mediated genes is dependent on the nuclear transcription factor, hypoxia‐inducible factor (HIF)1α and HIF2α. HIF1α has been shown to be critical in maintaining the integrity of intestinal epithelial barrier during the pathogenesis of colitis. In the present study, the role of HIF2α was assessed. Mice with a colonic epithelium overexpression of HIF2α revealed that a chronic increase in HIF2α signaling triggers an inflammatory response as assessed by an increase in pro‐inflammatory mediators and colon histology. Interestingly, a robust increase in intestinal permeability compared to wild‐type littermates was observed. To identify direct target genes of HIF‐2α that could regulate the intestinal barrier function, gene expression profile using microarrays were performed. Several barrier protective genes were altered and functional studies demonstrated a direct role of HIF2α‐regulated barrier genes in promoting colon inflammation. The present study demonstrates a divergent role of HIF1α and HIF2α in regulating intestinal epithelium homeostasis and provides important implications in using HIF modulators as therapeutic modalities in IBD.