Abstract
Crohn disease (CD) ileal lesions are colonized by adherent-invasive E. coli (AIEC) that locally induce inflammation. Hypoxia inducible factor (HIF)-1alpha protein is expressed in acute and chronically inflamed site; however the molecular basis of this expression is not fully understood. The aim of the study was to access whether AIEC induce HIF-1α expression and to study the consequence of HIF-1α expression on the onset of Crohn disease pathogenesis. We show that HIF-1α is maximally expressed in inflamed ileal epithelium of CD-patients. CEACAM6, a protein that acts as a receptor of AIEC, is expressed in this particular condition. Using CEABAC 10 transgenic mice that express CEACAM6, we show that AIEC bacteria, but not non-pathogenic E. coli K12, induce the production of HIF-1alpha protein and the activation of VEGF/VEGFR signaling. Downstream analyses on human intestinal epithelial cells silenced for hif- 1α, highlight the crucial role of this protein in production of pro-angiogenic factors. This study highlights the crucial role of AIEC bacteria as promoter of inflammatory disorders of the gastrointestinal tract and provides clear evidence that HIF-1α protein plays a major role in mediating this effect.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Bacterial Adhesion
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Case-Control Studies
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism
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Crohn Disease / metabolism
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Crohn Disease / microbiology*
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Crohn Disease / pathology
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Escherichia coli / growth & development
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Escherichia coli / pathogenicity*
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Escherichia coli Infections / metabolism
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Escherichia coli Infections / microbiology
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Female
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Flagella / metabolism
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GPI-Linked Proteins / genetics
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GPI-Linked Proteins / metabolism
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Gene Silencing
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Ileum / metabolism
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Ileum / microbiology
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Ileum / pathology
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Immunohistochemistry
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / microbiology
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Intestinal Mucosa / pathology*
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Male
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Mice
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Mice, Transgenic
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Middle Aged
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Signal Transduction
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Toll-Like Receptor 5 / metabolism
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Young Adult
Substances
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Antigens, CD
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CEACAM6 protein, human
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Cell Adhesion Molecules
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GPI-Linked Proteins
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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TLR5 protein, human
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Toll-Like Receptor 5
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse