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COELIAC DISEASE |
1 Department of Biomedical Sciences and Biotechnology, 2nd Pediatric Clinic, University of Cagliari, Cagliari, Italy, and Division of Pediatric Gastroenterology and Nutrition, Mucosal Biology Research Centre, University of Maryland School of Medicine, Baltimore, USA
2 Department of Biomedical Sciences and Biotechnology, 2nd Pediatric Clinic, University of Cagliari, Cagliari, Italy
3 Center for Fluorescence Spectroscopy, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, USA, and Department of Oral Biochemistry and Molecular Biology, College of Dentistry, Pusan National University, Pusan 602-739, Korea
4 Division of Pediatric Gastroenterology and Nutrition, Mucosal Biology Research Centre, University of Maryland School of Medicine, Baltimore, USA
Correspondence to:
Correspondence to:
Dr A Fasano, Division of Pediatric Gastroenterology and Nutrition, University of Maryland School of Medicine, 685 W Baltimore St HSF Building, Room 465, Baltimore, MD 21201, USA;
afasano{at}peds.umaryland.edu
Background and aims: Despite the progress made in understanding the immunological aspects of the pathogenesis of coeliac disease (CD), the early steps that allow gliadin to cross the intestinal barrier are still largely unknown. The aim of this study was to establish whether gliadin activates a zonulin dependent enterocyte intracellular signalling pathway(s) leading to increased intestinal permeability.
Methods: The effect of gliadin on the enterocyte actin cytoskeleton was studied on rat intestinal epithelial (IEC-6) cell cultures by fluorescence microscopy and spectrofluorimetry. Zonulin concentration was measured on cell culture supernatants by enzyme linked immunosorbent assay. Transepithelial intestinal resistance (Rt) was measured on ex vivo intestinal tissues mounted in Ussing chambers.
Results: Incubation of cells with gliadin led to a reversible protein kinase C (PKC) mediated actin polymerisation temporarily coincident with zonulin release. A significant reduction in Rt was observed after gliadin addition on rabbit intestinal mucosa mounted in Ussing chambers. Pretreatment with the zonulin inhibitor FZI/0 abolished the gliadin induced actin polymerisation and Rt reduction but not zonulin release.
Conclusions: Gliadin induces zonulin release in intestinal epithelial cells in vitro. Activation of the zonulin pathway by PKC mediated cytoskeleton reorganisation and tight junction opening leads to a rapid increase in intestinal permeability.
Keywords: gliadin; enterocyte cytoskeleton; tight junction; intestinal permeability; coeliac disease
Abbreviations: CD, coeliac disease; Rt, transepithelial electrical resistance; Zot, zonula occludens toxin; tj, tight junctions; PKC, protein kinase C; BSA, bovine serum albumin; PBS, phosphate buffered saline; CV, coefficient of variation
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