Mucosal inflammation downregulates PHD1 expression promoting a barrier-protective HIF-1 alpha response in ulcerative colitis patients

Eric Brown, Catherine Rowan, Moritz J. Strowitzki, Raphael R. Fagundes, Klaas Nico Faber, Annemarie Guentsch, Doug N. Halligan, Julia Kugler, Fiona Jones, Chee T. Lee, Glen Doherty, Cormac T. Taylor*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

Abstract

The HIF hydroxylase enzymes (PHD1-3 and FIH) are cellular oxygen-sensors which confer hypoxic-sensitivity upon the hypoxia-inducible factors HIF-1α and HIF-2α. Microenvironmental hypoxia has a strong influence on the epithelial and immune cell function through HIF-dependent gene expression and consequently impacts upon the course of disease progression in ulcerative colitis (UC), with HIF-1α being protective while HIF-2α promotes disease. However, little is known about how inflammation regulates hypoxia-responsive pathways in UC patients. Here we demonstrate that hypoxia is a prominent microenvironmental feature of the mucosa in UC patients with active inflammatory disease. Furthermore, we found that inflammation drives transcriptional programming of the HIF pathway including downregulation of PHD1 thereby increasing the tissue responsiveness to hypoxia and skewing this response toward protective HIF-1 over detrimental HIF-2 activation. We identified CEBPα as a transcriptional regulator of PHD1 mRNA expression which is downregulated in both inflamed tissue derived from patients and in cultured intestinal epithelial cells treated with inflammatory cytokines. In summary, we propose that PHD1 downregulation skews the hypoxic response toward enhanced protective HIF-1α stabilization in the inflamed mucosa of UC patients.

Original languageEnglish
Pages (from-to)3732-3742
Number of pages11
JournalThe FASEB Journal
Volume34
Issue number3
DOIs
Publication statusPublished - 16-Jan-2020

Keywords

  • colitis
  • epithelium
  • hypoxia
  • inflammation
  • PHD1
  • BINDING-PROTEIN ISOFORMS
  • GENE-EXPRESSION
  • HYPOXIA
  • ACTIVATION
  • PATHWAY
  • MODEL

Cite this