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

Authors
  • Solanki, Sumeet1
  • Devenport, Samantha N1, 2
  • Ramakrishnan, Sadeesh K1
  • Shah, Yatrik M1, 3
  • 1 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
  • 2 Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan.
  • 3 Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan.
Type
Published Article
Journal
AJP Gastrointestinal and Liver Physiology
Publisher
American Physiological Society
Publication Date
Aug 01, 2019
Volume
317
Issue
2
Identifiers
DOI: 10.1152/ajpgi.00081.2019
PMID: 31241981
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Hypoxia is a notable feature of inflammatory bowel disease and chronic induction of hypoxia-inducible factor (HIF)-1α and HIF-2α (endothelial PAS domain protein 1, EPAS1) play important, but opposing, roles in its pathogenesis. While activation of HIF-1α decreases intestinal inflammation and is beneficial in colitis, activation of HIF-2α exacerbates colitis and increases colon carcinogenesis in animal models, primarily due to the role of epithelial HIF-2α in mounting a potent inflammatory response. Previous work from our laboratory showed that mice overexpressing intestinal epithelial HIF-2α 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-2α to assess its role in mediating inflammatory response. Remarkably, activation of HIF-2α 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-2α was sufficient to exacerbate colitis. These data confirm our previous finding that epithelial HIF-2α mediates inflammatory response and demonstrates that activation of HIF-2α 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)-1α and HIF-2α are notable features of IBD. HIF-1α has well-characterized protective roles in IBD; however, the role of HIF-2α has been less studied. Using novel HIF-2α mouse models, we show that activation of HIF-2α in intestinal epithelial cells is sufficient to exacerbate colitis.

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