Endothelial PAS domain protein 1 activates the inflammatory response in the intestinal epithelium to promote colitis in mice

Abstract

Background & aims: Hypoxic inflammation (decreased oxygen tension at sites of inflammation) is a feature of inflammatory bowel disease (IBD). The hypoxia response is mediated by the transcription factors hypoxia-inducible factor (HIF) 1α and endothelial PAS domain protein 1 (EPAS1 or HIF2α), which are induced in intestinal tissues of patients with IBD. HIF1α limits intestinal barrier dysfunction, but the role of EPAS1 has not been assessed under conditions of hypoxic inflammation or in models of IBD.

Methods: Acute colitis was induced by administration of Citrobacter rodentium or dextran sulfate sodium (DSS) to transgenic hypoxia reporter mice (oxygen-dependent degradation-luciferase), mice with conditional overexpression of Epas1 (Epas1(LSL/LSL)), mice with intestinal epithelium-specific deletion of Epas1 (Epas1(ΔIE) ), or wild-type littermates (controls). Colon tissues from these mice and from patients with ulcerative colitis or Crohn's disease were assessed by histologic and immunoblot analyses, immunohistochemistry, and quantitative polymerase chain reaction.

Results: Levels of hypoxia and EPAS1 were increased in colon tissues of mice after induction of colitis and patients with ulcerative colitis or Crohn's disease compared with controls. Epas1(ΔIE) mice had attenuated colonic inflammation and were protected from DSS-induced colitis. Intestine-specific overexpression of EPAS1, but not HIF-1α, led to spontaneous colitis, increased susceptibility to induction of colitis by C rodentium or DSS, and reduced survival times compared with controls. Disruption of intestinal epithelial EPAS1 attenuated the inflammatory response after administration of DSS or C rodentium, and intestine-specific overexpression of EPAS1 increased this response. We found EPAS1 to be a positive regulator of tumor necrosis factor-α production by the intestinal epithelium. Blocking tumor necrosis factor-α completely reduced hypoxia-induced intestinal inflammation.

Conclusions: EPAS1 is a transcription factor that activates mediators of inflammation, such as tumor necrosis factor-α, in the intestinal epithelium and promotes development of colitis in mice.

Keywords: CD; Crohn's disease; DMOG; DSS; EPAS1; HIF; IBD; IL; MAZ; Mouse Model; NF-κB; ODD; Oxygen; PHD; TNF; UC; WT; dextran sulfate sodium; dimethyloxaloylglycine; endothelial PAS domain protein 1; hypoxia-inducible factor; inflammatory bowel disease; interleukin; myc-associated zinc finger protein; nuclear factor κB; oxygen-dependent degradation; prolyl hydroxylase; tumor necrosis factor; ulcerative colitis; wild type.