Journal
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
Volume 468, Issue 1, Pages 77-84Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00424-015-1722-4
Keywords
HIF-1 alpha; Hypoxia; Colitis; Inflammatory bowel disease; Hydroxylase; Immune cells
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Hypoxia is a hallmark of chronically inflamed tissue. Hypoxia develops from vascular dysfunction and increased oxygen consumption by infiltrating leukocytes. With respect to inflammatory bowel disease (IBD), hypoxia is likely to be of particular importance: Impairment of the intestinal barrier during IBD allows anoxia from the lumen of the gut to spread to formerly normoxic tissue. In addition, disturbed perfusion of inflamed tissue and a higher oxygen demand of infiltrating immune cells lead to low oxygen levels in inflamed mucosal tissue. Here, cells become hypoxic and must now adapt to this condition. The hypoxia inducible factor (HIF)-1 complex is a key transcription factor for cellular adaption to low oxygen tension. HIF-1 is a heterodimer formed by two subunits: HIF-alpha (either HIF-1 alpha or HIF-2 alpha) and HIF-1 beta. Under normoxic conditions, hydroxylation of the HIF-alpha subunit by specific oxygen-dependent prolyl hydroxylases (PHDs) leads to ubiquitin proteasome-dependent degradation. Under hypoxic conditions, however, PHD activity is inhibited; thus, HIF-alpha can translocate into the nucleus, dimerize with HIF-1 beta, and bind to hypoxia-responsive elements of HIF-1 target genes. So far, most studies have addressed the function of HIF-1 alpha in intestinal epithelial cells and the effect of HIF stabilization by PHD inhibitors in murine models of colitis. Furthermore, the role of HIF-1 alpha in immune cells becomes more and more important as T cells or dendritic cells for which HIF-1 is of critical importance are highly involved in the pathogenesis of IBD. This review will summarize the function of HIF-1 alpha and the therapeutic prospects for targeting the HIF pathway in intestinal mucosal inflammation.
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