title: Enterocyte proliferation and signaling are constitutively altered in celiac disease.
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.
authors.affiliation: 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.
authors.forename: Merlin
authors.initials: M
authors.lastname: Nanayakkara
authors.forename: Giuliana
authors.initials: G
authors.lastname: Lania
authors.forename: Mariantonia
authors.initials: M
authors.lastname: Maglio
authors.forename: Roberta
authors.initials: R
authors.lastname: Kosova
authors.forename: Marco
authors.initials: M
authors.lastname: Sarno
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gaito
authors.forename: Valentina
authors.initials: V
authors.lastname: Discepolo
authors.forename: Riccardo
authors.initials: R
authors.lastname: Troncone
authors.forename: Salvatore
authors.initials: S
authors.lastname: Auricchio
authors.forename: Renata
authors.initials: R
authors.lastname: Auricchio
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Barone
mesh_terms: D000293:Adolescent; D001706:Biopsy; D002446:Celiac Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D020895:Enterocytes / Q000378:metabolism* / Q000473:pathology*; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007223:Infant; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases