Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease. Issue 2 (24th August 2011)

• Record Type: Journal Article
• Authors: Schumann, Michael; Günzel, Dorothee; Buergel, Nataly; Richter, Jan F; Troeger, Hanno; May, Claudia; Fromm, Anja; Sorgenfrei, Detlef; Daum, Severin; Bojarski, Christian; Heyman, Martine; Zeitz, Martin; Fromm, Michael; Schulzke, Joerg-Dieter
• Is Part Of: Gut. Volume 61:Issue 2(2012)
• Page Start: 220
• Page End: 228
• Publication Date: 2011-08-24
• Subjects: Celiac disease -- epithelial barrier -- Par-3 -- tight junction -- apoptosis -- gastrointestinal lymphoma -- gamma delta t cells -- lamina proprial lymphocytes -- coeliac disease -- enteropathy -- endoscopy -- new imaging technologies -- confocal laser endomicroscopy -- chromoendoscopy -- endoscopic retrograde pancreatography -- endoscopic ultrasonography -- endoscopic polypectomy -- adenoma -- endoscopic procedures -- gut immunology -- epithelial permeability -- epithelial transport -- HIV/AIDS -- Crohn's disease -- inflammatory bowel disease -- mucosal immunology -- HIV-related gastrointestinal disease -- Helicobacter pylori -- acid-related diseases -- non-ulcer dyspepsia -- genetic polymorphisms -- gastric neoplasia -- inflammation -- IBD -- 5-aminosalicylic acid (5-ASA) -- inflammatory mechanisms -- radiation enteritis -- apoptosis; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2011-300123
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background: Epithelial barrier defects are well known in coeliac disease, but the mechanisms are only poorly defined. It is unclear, whether barrier disturbance reflects upregulated epithelial transcytosis or paracellular leakage. Objective: To characterise the molecular structure and function of the epithelial tight junction (TJ) and mechanisms of its dysregulation. Methods: Molecular analysis of proteins involved in TJ assembly and their regulation was performed by western blotting and confocal microscopy correlated to electrophysiology. Results: A complex alteration of the composition of epithelial TJ proteins (with more pore-forming claudins like claudin-2 and a reduction in tightening claudins like claudin-3, -5 and -7) was found for protein expression and subcellular localisation, responsible for an increase in paracellular biotin-NHS uptake. In contrast, epithelial apoptosis was only moderately elevated (accounting for a minor portion of barrier defects) and epithelial gross lesions—for example, at cell extrusion zones, were absent. This TJ alteration was linked to an altered localisation/expression of proteins regulating TJ assembly, the polarity complex protein Par-3 and the serine-/threonine phosphatase PP-1. Conclusions: Changes in cell polarity proteins Par-3 and PP-1 are associated with altered expression and assembly of TJ proteins claudin-2, -3, -5 and -7 and ZO-1, causing paracellular leakage in active coeliac disease.