Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
3296228 | Gastroenterology | 2008 | 14 Pages |
Abstract
Background & Aims: Celiac disease is an immune-mediated enteropathy triggered by gliadin, a component of the grain protein gluten. Gliadin induces an MyD88-dependent zonulin release that leads to increased intestinal permeability, a postulated early element in the pathogenesis of celiac disease. We aimed to establish the molecular basis of gliadin interaction with intestinal mucosa leading to intestinal barrier impairment. Methods: α-Gliadin affinity column was loaded with intestinal mucosal membrane lysates to identify the putative gliadin-binding moiety. In vitro experiments with chemokine receptor CXCR3 transfectants were performed to confirm binding of gliadin and/or 26 overlapping 20mer α-gliadin synthetic peptides to the receptor. CXCR3 protein and gene expression were studied in intestinal epithelial cell lines and human biopsy specimens. Gliadin-CXCR3 interaction was further analyzed by immunofluorescence microscopy, laser capture microscopy, real-time reverse-transcription polymerase chain reaction, and immunoprecipitation/Western blot analysis. Ex vivo experiments were performed using C57BL/6 wild-type and CXCR3â/â mouse small intestines to measure intestinal permeability and zonulin release. Results: Affinity column and colocalization experiments showed that gliadin binds to CXCR3 and that at least 2 α-gliadin 20mer synthetic peptides are involved in this binding. CXCR3 is expressed in mouse and human intestinal epithelia and lamina propria. Mucosal CXCR3 expression was elevated in active celiac disease but returned to baseline levels following implementation of a gluten-free diet. Gliadin induced physical association between CXCR3 and MyD88 in enterocytes. Gliadin increased zonulin release and intestinal permeability in wild-type but not CXCR3â/â mouse small intestine. Conclusions: Gliadin binds to CXCR3 and leads to MyD88-dependent zonulin release and increased intestinal permeability.
Keywords
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Authors
Karen M. Lammers, Ruliang Lu, Julie Brownley, Bao Lu, Craig Gerard, Karen Thomas, Prasad Rallabhandi, Terez Shea-Donohue, Amir Tamiz, Sefik Alkan, Sarah Netzel-Arnett, Toni Antalis, Stefanie N. Vogel, Alessio Fasano,