Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease.

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

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.

Afiliación

Schumann M; Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité Berlin, Berlin, Germany.

Gut ; 61(2): 220-8, 2012 Feb.

Article en En | MEDLINE | ID: mdl-21865402

RESUMEN

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.

Asunto(s)

Enfermedad Celíaca/metabolismo; Proteínas de Ciclo Celular/metabolismo; Polaridad Celular; Mucosa Intestinal/metabolismo; Proteínas de la Membrana/metabolismo; Proteína Fosfatasa 1/metabolismo; Uniones Estrechas/metabolismo; Proteínas Adaptadoras Transductoras de Señales; Apoptosis; Biotinilación; Western Blotting; Estudios de Casos y Controles; Enfermedad Celíaca/patología; Enfermedad Celíaca/fisiopatología; Proteínas de Ciclo Celular/fisiología; Claudinas/metabolismo; Humanos; Mucosa Intestinal/química; Proteínas de la Membrana/fisiología; Microscopía Confocal; Fosfoproteínas/metabolismo; Reacción en Cadena de la Polimerasa; Proteína Fosfatasa 1/fisiología; Uniones Estrechas/química; Proteína de la Zonula Occludens-1

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad Celíaca / Polaridad Celular / Proteínas de Ciclo Celular / Uniones Estrechas / Proteína Fosfatasa 1 / Mucosa Intestinal / Proteínas de la Membrana Tipo de estudio: Observational_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Gut Año: 2012 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido

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