| First Author | Solanki S | Year | 2019 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 317 |
| Issue | 2 | Pages | G98-G107 |
| PubMed ID | 31241981 | Mgi Jnum | J:307422 |
| Mgi Id | MGI:6711155 | Doi | 10.1152/ajpgi.00081.2019 |
| Citation | Solanki S, et al. (2019) Temporal induction of intestinal epithelial hypoxia-inducible factor-2alpha is sufficient to drive colitis. Am J Physiol Gastrointest Liver Physiol 317(2):G98-G107 |
| abstractText | Hypoxia is a notable feature of inflammatory bowel disease and chronic induction of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (endothelial PAS domain protein 1, EPAS1) play important, but opposing, roles in its pathogenesis. While activation of HIF-1alpha decreases intestinal inflammation and is beneficial in colitis, activation of HIF-2alpha exacerbates colitis and increases colon carcinogenesis in animal models, primarily due to the role of epithelial HIF-2alpha in mounting a potent inflammatory response. Previous work from our laboratory showed that mice overexpressing intestinal epithelial HIF-2alpha led to massive intestinal inflammation and decreased survival. As oxygen homeostasis and HIFs are critical in embryonic development, it is not clear whether the observed intestinal inflammatory response was secondary to developmental defects. To address this question, the present study used a mouse model to temporally modulate expression of intestinal epithelial HIF-2alpha to assess its role in mediating inflammatory response. Remarkably, activation of HIF-2alpha in intestinal epithelial cells in adult mice increased expression of proinflammatory mediators; however, no decrease in survival was observed. Furthermore, in an acute model of colitis, activation of HIF-2alpha was sufficient to exacerbate colitis. These data confirm our previous finding that epithelial HIF-2alpha mediates inflammatory response and demonstrates that activation of HIF-2alpha is sufficient to exacerbate colitis.NEW & NOTEWORTHY Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestinal tract. Hypoxia and activation of its downstream transcription factors hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha are notable features of IBD. HIF-1alpha has well-characterized protective roles in IBD; however, the role of HIF-2alpha has been less studied. Using novel HIF-2alpha mouse models, we show that activation of HIF-2alpha in intestinal epithelial cells is sufficient to exacerbate colitis. |
