Growth factor-like activity of gliadin, an alimentary protein: implications for coeliac disease

• Published in: Gut Vol. 56; no. 4; pp. 480 - 488
• Main Authors: Barone, Maria V, Gimigliano, Anna, Castoria, Gabriella, Paolella, Giovanni, Maurano, Francesco, Paparo, Franco, Maglio, Maria, Mineo, Alba, Miele, Erasmo, Nanayakkara, Merlin, Troncone, Riccardo, Auricchio, Salvatore
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01-04-2007; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Actins - metabolism; Apoptosis; Apoptosis - drug effects; Bands; Biological and medical sciences; Caco-2 Cells; Celiac disease; Celiac Disease - metabolism; Celiac Disease - pathology; Cell Cycle - drug effects; Cell growth; Cell Line; Cell Proliferation - drug effects; Cloning; Coeliac Disease; Cytoskeleton - drug effects; EGF; EGFR; Endocytosis - drug effects; Epidermal growth factor; Epidermal Growth Factor - metabolism; epidermal growth factor receptor; Gastroenterology. Liver. Pancreas. Abdomen; Gliadin - metabolism; Gliadin - pharmacology; Humans; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Ligands; Medical sciences; Organ Culture Techniques; Other diseases. Semiology; Pathogenesis; PDGF; peptic-tryptic digest of lactoalbumin; peptic-tryptic digests of gliadin; Peptides; Phosphorylation; Platelet derived Growth Factor; Polyclonal antibodies; PTG; PTL; Receptor, Epidermal Growth Factor - drug effects; Receptor, Epidermal Growth Factor - metabolism; Receptor, Epidermal Growth Factor - physiology; Signal transduction; Small intestine; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Triticum aestivum; Immunopathology; Pathogenesis; Mucosa; Coeliac disease; Small intestine; Protein; Epidermal growth factor; Intestinal malabsorption; Biopsy; Gliadin; Digestive diseases; Intestinal disease; Cytoskeleton; Growth factor
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2005.086637

Background: Gliadins, a family of wheat proteins, are central to the pathogenesis of celiac disease (CD). In addition to ‘immunogenic’ effects, gliadin directly affects cultured cells and intestine preparations, and produces damage in vivo, via a separate ‘toxic’ peptide, such as A-gliadin p31–43 (P31–43). Aims: Understanding the molecular mechanisms underlying direct non T-cell mediated effects of gliadin peptides, and assessing their potential role in promoting CD. Method: Gliadin effects were tested on a number of cell lines and on cultured mucosa samples by evaluating cytoskeleton rearrangements, endocytosis, proliferation and apoptosis. Standard biochemical methods were used to assess prolonged epidermal growth factor receptor (EGFR) activation. Results: Crude gliadin peptic-tryptic peptides (PTG], or P31–43 alone, fully reproduce the effects of epidermal growth factor (EGF] on actin cytosketon, cell cycle and cell proliferation of various cell lines. Inhibitor studies demonstrate the role of EGFR in the early response to gliadin exposure, pointing to activation of the EGFR pathway. Peptide P31–43 is not similar to any EGFR ligand, but can delay inactivation of the EGFR interfering with its endocytosis. Gliadin-induced delay of EGFR endocytosis in cultured intestinal biopsies, together with S-phase entry of epithelial intestinal cells, confirm a role for EGFR activation in CD. Conclusion: The ability of gliadin peptides to delay EGFR inactivation through interference with the endocytic pathway suggests a model where gliadin fragments amplify the effects of trace amounts of EGF, and possibly of other growth factors, by prolonging receptor activation. The results, using cultures of coeliac intestinal biopsies, highlight the role of the EGF pathway in establishing and maintaining the typical atrophic and proliferative alterations of the small intestine in CD.