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Enterocyte Proliferation and Signaling Are Constitutively Altered in Celiac Disease
Authors:Merlin Nanayakkara  Giuliana Lania  Mariantonia Maglio  Roberta Kosova  Marco Sarno  Alessandra Gaito  Valentina Discepolo  Riccardo Troncone  Salvatore Auricchio  Renata Auricchio  Maria Vittoria Barone
Institution:1. Department of Traslational Medicine (section of Pediatrics) and ELFID (European Laboratory for the Investigation of Food Induced Disease), University of Naples, Federico II, Naples, Italy.; 2. Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.; Boston University Goldman School of Dental Medicine, United States of America,
Abstract:Celiac disease (CD) occurs frequently, and is caused by ingestion of prolamins from cereals in subjects with a genetic predisposition. The small intestinal damage depends on an intestinal stress/innate immune response to certain gliadin peptides (e.g., A-gliadin P31-43) in association with an adaptive immune response to other gliadin peptides (e.g., A-gliadin P57-68). Gliadin and peptide P31-43 affect epithelial growth factor receptor (EGFR) signaling and CD enterocyte proliferation. The reason why the stress/innate immune and proliferative responses to certain gliadin peptides are present in CD and not in control intestine is so far unknown. The aim of this work is to investigate if, in CD, a constitutive alteration of enterocyte proliferation and signaling exists that may represent a predisposing condition to the damaging effects of gliadin. Immunofluorescence and immunohistochemistry were used to study signaling in CD fibroblasts and intestinal biopsies. Western blot (WB) analysis, immunoprecipitation, and quantitative PCR were also used. We found in CD enterocytes enhancement of both proliferation and Epidermal Growth Factor Receptor (EGFR)/ligand system. In CD enterocytes and fibroblasts we found increase of the phosphorylated downstream signaling molecule Extracellular Signal Regulated Kinase (ERK); block of the ERK activation normalizes enterocytes proliferation in CD mucosa. In conclusion the same pathway, which gliadin and gliadin peptide P31-43 can interfere with, is constitutively altered in CD cells. This observation potentially explains the specificity of the damaging effects of certain gliadin peptides on CD intestine.
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