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Gut. 2012 Feb;61(2):220-8. doi: 10.1136/gutjnl-2011-300123. Epub 2011 Aug 24.

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

Author information

1
Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité Berlin, Berlin, Germany.

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.

PMID:
21865402
DOI:
10.1136/gutjnl-2011-300123
[Indexed for MEDLINE]

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