Document Detail

Requirement of Cellular Prion Protein for Intestinal Barrier Function and Mislocalization in Patients with Inflammatory Bowel Disease.
MedLine Citation:
PMID:  22446194     Owner:  NLM     Status:  Publisher    
BACKGROUND & AIMS: Cell adhesion is one function regulated by cellular prion protein (PrP(c)), a ubiquitous, glycosylphosphatidylinositol-anchored glycoprotein. PrP(c) is located in cell-cell junctions and interacts with desmosome proteins in the intestinal epithelium. We investigated its role in intestinal barrier function. METHODS: We analyzed permeability and structure of cell-cell junctions in intestine tissues from PrP(c) knockout (PrP(c-/-)) and wild-type mice. PrP(c) expression was knocked down in cultured human Caco-2/TC7 enterocytes using small hairpin RNAs. We analyzed colon samples from 24 patients with inflammatory bowel disease (IBD). RESULTS: Intestine tissues from PrP (c-/-)mice had greater paracellular permeability than from wild-type mice (105.9±13.4 vs 59.6±10.1 mg/ml FITC-dextran flux; P<.05) and impaired intercellular junctions. PrP (c-/-)mice did not develop spontaneous disease, but were more sensitive than wild-type mice to induction of colitis with dextran sulfate (32% mortality vs 4%, respectively; P=.0033). Such barrier defects were observed also in Caco-2/TC7 enterocytes following PrP(c) knockdown; the cells had increased paracellular permeability (1.5-fold over 48 h; P<.001) and reduced transepithelial electrical resistance (281.1±4.9 vs 370.6±5.7 Ω/cm(2); P<.001). Monolayer shape and cell-cell junctions were altered in cultures of PrP(c) knockdown cells; levels of E-cadherin, desmoplakin, plakoglobin, claudin-4, occludin, ZO-1, and tricellulin were decreased at cell contacts. Cell shape and junctions were restored upon PrP(c) re-expression. Levels of PrP(c) were decreased at cell-cell junctions in colonic epithelia from patients with Crohn's disease or ulcerative colitis. CONCLUSION: PrP(c) regulates intestinal epithelial cell-cell junctions and barrier function. Its localization is altered in colonic epithelia from patients with IBD, supporting the concept that disrupted barrier function contributes to this disorder.
Constance S V Petit; Frédérick Barreau; Laura Besnier; Pierre Gandille; Béatrice Riveau; Danielle Chateau; Maryline Roy; Dominique Berrebi; Magali Svrcek; Philippe Cardot; Monique Rousset; Caroline Clair; Sophie Thenet
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-22
Journal Detail:
Title:  Gastroenterology     Volume:  -     ISSN:  1528-0012     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-26     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S 872, Paris, F-75006 France; INSERM, U 872, Paris, F-75006 France; Université Paris Descartes-Paris 5, UMR S 872, Paris, F-75006 France.
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