title: Fundamental role for HIF-1α in constitutive expression of human β defensin-1.
abstract: Antimicrobial peptides are secreted by the intestinal epithelium to defend from microbial threats. The role of human β defensin-1 (hBD-1) is notable because its gene (beta-defensin 1 (DEFB1)) is constitutively expressed and its antimicrobial activity is potentiated in the low-oxygen environment that characterizes the intestinal mucosa. Hypoxia-inducible factor (HIF) is stabilized even in healthy intestinal mucosa, and we identified that epithelial HIF-1α maintains expression of murine defensins. Extension to a human model revealed that basal HIF-1α is critical for the constitutive expression of hBD-1. Chromatin immunoprecipitation identified HIF-1α binding to a hypoxia response element in the DEFB1 promoter whose importance was confirmed by site-directed mutagenesis. We used 94 human intestinal samples to identify a strong expression correlation between DEFB1 and the canonical HIF-1α target GLUT1. These findings indicate that basal HIF-1α is critical for constitutive expression of enteric DEFB1 and support targeting epithelial HIF for restoration and maintenance of intestinal integrity.
authors: Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: C J
authors: CJ
authors: Kelly
authors: L E
authors: LE
authors: Glover
authors: E L
authors: EL
authors: Campbell
authors: D J
authors: DJ
authors: Kominsky
authors: S F
authors: SF
authors: Ehrentraut
authors: B E
authors: BE
authors: Bowers
authors: A J
authors: AJ
authors: Bayless
authors: B J
authors: BJ
authors: Saeedi
authors: S P
authors: SP
authors: Colgan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018938:Caco-2 Cells; D006801:Humans; D000860:Hypoxia / Q000276:immunology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D015533:Transcriptional Activation; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C406407:DEFB1 protein, human; C492009:GIPC1 protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D023083:beta-Defensins