title: H1 and PAR2 receptors enhance delivery of immune-competent cells and molecules by interrupting E-cadherin adhesion in epithelia.
abstract: The lung's epithelial surface is at the same time vitally exchanging gas with the environment and acting as a barrier that protects the organism from the environment. We hypothesized that activation of epithelial-cell G-protein-coupled receptors for immune-defense molecules would temporarily interrupt cadherin-dependent cell-cell adhesion of epithelial cells and thereby focally and temporarily compromise the epithelial barrier to facilitate delivery of other immune molecules and cells to challenged sites. Activation of type 1 histamine or type 2 PAR receptors on the basolateral surface of primary airway epithelial cells or L-cells expressing E-cadherin interrupted cadherin adhesion and caused approximately a 50% decrease in the epithelial barrier for 2-3 minutes. Given basic biochemical observations of others, we further hypothesized that activation of the receptors altered the barrier by phosphorylating tyrosines on an essential cadherin-complex component, beta-catenin. Y-F mutations in beta-catenin completely blocked the effects of activating the same receptors on cadherin-dependent adhesion and on the epithelial barrier. Hence, G-protein-coupled receptors responding to immune-defense molecules temporarily and focally interrupt the lung epithelial barrier by compromising cadherin-based adhesion.
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Newton Rd., Iowa City, IA 52242, USA. michael-shasby@uiowa.edu
authors.forename: D Michael
authors.initials: DM
authors.lastname: Shasby
authors.forename: Michael C
authors.initials: MC
authors.lastname: Winter
mesh_terms: D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D004285:Dogs; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects; D007668:Kidney / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology; D010539:Permeability; D010766:Phosphorylation; D044464:Receptor, PAR-2 / Q000819:agonists / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D009842:Oligopeptides; D044464:Receptor, PAR-2; D011969:Receptors, Histamine H1; D051176:beta Catenin; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; D014443:Tyrosine