title: Regulation of oxidant-induced intestinal permeability by metalloprotease-dependent epidermal growth factor receptor signaling.
abstract: Inflammatory bowel disease (IBD) affects more than 1 million Americans with more than 30,000 new cases diagnosed each year. IBD increases patient morbidity and susceptibility to colorectal cancer, yet its etiology remains unknown. Current models identify two key determinants of IBD pathogenesis: hyperpermeability of the gut epithelial barrier to bacterial products and an abnormal immune response to these products. Two factors seem critical for hyperpermeability: oxidant-induced stress and proinflammatory cytokines (e.g., tumor necrosis factor-alpha). The aim of this study was to investigate the role of oxidant stress-mediated transactivation of the epidermal growth factor receptor (EGFR) in intestinal hyperpermeability. This study used the Caco-2 human colonic epithelial cell in vitro model of intestinal epithelium. Cells were grown on inserts for permeability and signaling studies and glass coverslips for microscopy studies. show that oxidant-induced intestinal hyperpermeability can be blocked by specific inhibitors of the EGFR, tumor necrosis factor convertase (TACE) metalloprotease, transforming growth factor (TGF)-alpha, and mitogen-activated protein kinases, especially extracellular signal-regulated kinase 1/2. We also show that oxidant initiates these signaling events, in part by causing translocation of TACE to cell-cell contact zones. In this study, our data identify a novel mechanism for oxidant-induced intestinal hyperpermeability relevant to IBD. We propose a new intestinal permeability model in which oxidant transactivates EGFR signaling by activation of TACE and cleavage of precursor TGF-alpha. These data could have a significant effect on our view of IBD pathogenesis and provide new therapeutic targets for IBD treatment.
authors.affiliation: Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, 1725 W. Harrison, Suite 206, Chicago, IL 60612, USA. christopher_b_forsyth@rush.edu
authors.forename: C B
authors.initials: CB
authors.lastname: Forsyth
authors.forename: A
authors.initials: A
authors.lastname: Banan
authors.forename: A
authors.initials: A
authors.lastname: Farhadi
authors.forename: J Z
authors.initials: JZ
authors.lastname: Fields
authors.forename: Y
authors.initials: Y
authors.lastname: Tang
authors.forename: M
authors.initials: M
authors.lastname: Shaikh
authors.forename: L J
authors.initials: LJ
authors.lastname: Zhang
authors.forename: P A
authors.initials: PA
authors.lastname: Engen
authors.forename: A
authors.initials: A
authors.lastname: Keshavarzian
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism / Q000502:physiology; D000072198:ADAM17 Protein; D015153:Blotting, Western; D018938:Caco-2 Cells; D004815:Epidermal Growth Factor / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D015212:Inflammatory Bowel Diseases / Q000503:physiopathology; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D045726:Metalloproteases / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology; D010539:Permeability / Q000187:drug effects*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: D016877:Oxidants; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D006861:Hydrogen Peroxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human