1. Mucosal inflammation downregulates PHD1 expression promoting a barrier-protective HIF-1α response in ulcerative colitis patients
- Author
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Catherine Rowan, Eric Brown, Klaas Nico Faber, Cormac T. Taylor, Julia Kugler, Fiona Jones, Doug N. Halligan, Moritz J. Strowitzki, Annemarie Güntsch, Glen A. Doherty, Raphael R. Fagundes, Chee T. Lee, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
- Subjects
0301 basic medicine ,Chromatin Immunoprecipitation ,colitis ,Blotting, Western ,Inflammation ,Biochemistry ,Proinflammatory cytokine ,Hypoxia-Inducible Factor-Proline Dioxygenases ,ACTIVATION ,PATHWAY ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,BINDING-PROTEIN ISOFORMS ,Genetics ,Transcriptional regulation ,Medicine ,Humans ,PHD1 ,RNA, Messenger ,Colitis ,Molecular Biology ,GENE-EXPRESSION ,business.industry ,hypoxia ,Computational Biology ,Hypoxia (medical) ,medicine.disease ,Hypoxia-Inducible Factor 1, alpha Subunit ,Inflammatory Bowel Diseases ,Ulcerative colitis ,Immunohistochemistry ,Epithelium ,MODEL ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,Colitis, Ulcerative ,medicine.symptom ,Caco-2 Cells ,business ,epithelium ,030217 neurology & neurosurgery ,Biotechnology - 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.
- Published
- 2019