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

Brown, E., Rowan, C., Strowitzki, M. J., Fagundes, R. R., Faber, K. N., Guentsch, A., Halligan, D. N., Kugler, J., Jones, F., Lee, C. T., Doherty, G. & Taylor, C. T., 16-Jan-2020, In : The FASEB Journal. 11 p.

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  • Mucosal inflammation downregulates PHD1 expression promoting a barrier‐protective HIF‐1α response in ulcerative colitis patients

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DOI

  • 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

The HIF hydroxylase enzymes (PHD1-3 and FIH) are cellular oxygen-sensors which confer hypoxic-sensitivity upon the hypoxia-inducible factors HIF-1 alpha and HIF-2 alpha. 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-1 alpha being protective while HIF-2 alpha 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 CEBP alpha 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-1 alpha stabilization in the inflamed mucosa of UC patients.

Original languageEnglish
Number of pages11
JournalThe FASEB Journal
Publication statusPublished - 16-Jan-2020

    Keywords

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

ID: 112600159