Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function

Department of Biomedical Sciences and Biotechnology, 2nd Pediatric Clinic, University of Cagliari, Cagliari, Italy.
Gut (Impact Factor: 14.66). 03/2003; 52(2):218-23.
Source: PubMed


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.
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.
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.
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.

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    • "TNFα signalling activates myosin light chain kinase (MLCK) and tight junction remodelling leading to loss of barrier function [32], [33]. It is noteworthy that gliadin peptides can also increase permeability by innate mechanisms amplifying the circuit of mucosal damage [34], [35], [36], [37]. "
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    ABSTRACT: Systemic administration of polyinosinic:polycytidylic acid (poly I:C), mimics virally-induced activation of TLR3 signalling causing acute small intestine damage, but whether and how mucosal administration of poly I:C causes enteropathy is less clear. Our aim was to investigate the inflammatory pathways elicited after intraluminal administration of poly I:C and determine acute and delayed consequences of this locally induced immune activation. Intraluminal poly I:C induced rapid mucosal immune activation in C57BL/6 mice involving IFNβ and the CXCL10/CXCR3 axis, that may drive inflammation towards a Th1 profile. Intraluminal poly I:C also caused enteropathy and gut dysfunction in gliadin-sensitive NOD-DQ8 mice, and this was prolonged by concomitant oral administration of gliadin. Our results indicate that small intestine pathology can be induced in mice by intraluminal administration of poly I:C and that this is exacerbated by subsequent oral delivery of a relevant dietary antigen.
    PLoS ONE 06/2014; 9(6):e99236. DOI:10.1371/journal.pone.0099236 · 3.23 Impact Factor
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    • "Specifically the storage proteins (prolamins) gliadin (wheat), secalin (rye), and hordein (barley) have been shown to have toxic effects on intestinal cells in gluten sensitive people. The toxic effects of these prolamins include the reduction of F-actin, inhibition of cellular growth, premature cell death, the rearrangement of the cytoskeleton, and increased small bowel permeability (5). "
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    ABSTRACT: Over the last five decades the association between coeliac disease and other autoimmune disorders such as autoimmune thyroid disease or diabetes mellitus type 1 has been well established through many studies and to this day is subject to on-going clinical and scientific investigation worldwide. While no link has been established between celiac disease and type-2 diabetes mellitus, coeliac disease is common in patients with type 1 diabetes. The improvement of symptoms in patients with both conditions through dietary intervention, in the form of a gluten free diet, has been widely described within the literature. Our objectives were to review and synthesise the current knowledge on the nutritional treatment for patients with both conditions.
    Gastroenterology and hepatology from bed to bench 03/2014; 7(4):189-97.
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    • "Under physiological circumstances, intestinal epithelia are almost impermeable to macromolecules such as gliadin [12]. In CD, paracellular permeability is enhanced, and the integrity of TJ system is compromised [13–15]. The upregulation of zonulin, a recently described intestinal peptide involved in TJ regulation [16, 17], appears to be responsible, at least in part, for the increased gut permeability characteristic of CD [18]. "
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    ABSTRACT: Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Gluten is a protein component in wheat and other cereals like rye and barley. At present, the only available treatment is a strict gluten-free diet. Recent advances have increased our understanding of the molecular basis for this disorder. Last decade has seen new scientific developments in this disease and led to the formulation of new concepts of pathophysiology that offer possible targets for new treatments or interventions integrative to the gluten-free diet.
    Clinical and Developmental Immunology 10/2012; 2012(9):959061. DOI:10.1155/2012/959061 · 2.93 Impact Factor
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