Temporal induction of intestinal epithelial hypoxia-inducible factor (HIF)-2α is sufficient to drive colitis.

Hypoxia is a notable feature of inflammatory bowel disease and chronic induction of hypoxia-inducible factor (HIF)-1a and HIF-2a (Endothelial PAS Domain Protein 1, EPAS1) play important but opposing roles in its pathogenesis. While activation of HIF-1a decreases intestinal inflammation and is beneficial in colitis, activation of HIF-2a exacerbates colitis and increases colon carcinogenesis in animal models, primarily due to the role of epithelial HIF-2a in mounting a potent inflammatory response. Previous work from our laboratory showed that mice overexpressing intestinal epithelial HIF-2a led to massive intestinal inflammation and decreased survival. As oxygen homeostasis and HIFs are critical in embryonic development, it is not clear if the observed intestinal inflammatory response was secondary to developmental defects. To address this question, the present study utilized a mouse model to temporally modulate expression of intestinal epithelial HIF-2a to assess its role in mediating inflammatory response. Remarkably, activation of HIF-2a in intestinal epithelial cells in adult mice increased expression of pro-inflammatory mediators, however, no decrease in survival was observed. Furthermore, in an acute model of colitis, activation of HIF-2a was sufficient to exacerbate colitis. These data confirm our previous finding that epithelial HIF-2a mediates inflammatory response and demonstrates that activation of HIF-2a is sufficient to exacerbate colitis. strates that activation of HIF-2a is sufficient to exacerbate colitis.