undigested gliadin peptide activates innate immunity and proliferative signaling in enterocytes: the role in celiac disease

• Published in: The American journal of clinical nutrition Vol. 98; no. 4; pp. 1123 - 1135
• Main Authors: Nanayakkara, Merlin, Lania, Giuliana, Maglio, Mariantonia, Discepolo, Valentina, Sarno, Marco, Gaito, Alessandra, Troncone, Riccardo, Auricchio, Salvatore, Auricchio, Renata, Barone, Maria Vittoria
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Clinical Nutrition 01.10.2013; American Society for Nutrition; American Society for Clinical Nutrition, Inc
• Subjects: antibodies; Antibodies - pharmacology; Biological and medical sciences; biopsy; Caco-2 Cells; Celiac disease; Celiac Disease - immunology; Celiac Disease - pathology; Cell growth; cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; clinical nutrition; enterocytes; Enterocytes - immunology; Enterocytes - pathology; Epidermal Growth Factor - genetics; Epidermal Growth Factor - pharmacology; Epidermal Growth Factor - physiology; epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - physiology; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation - drug effects; gliadin; Gliadin - immunology; Gliadin - pharmacology; growth factors; human cell lines; Humans; Immune system; Immunity, Innate; ingestion; innate immunity; interleukin-15; Interleukin-15 - genetics; Interleukin-15 - pharmacology; Interleukin-15 - physiology; Interleukin-15 Receptor alpha Subunit - antagonists & inhibitors; Interleukin-15 Receptor alpha Subunit - genetics; Interleukin-15 Receptor alpha Subunit - physiology; Medical sciences; Other diseases. Semiology; patients; Peptide Fragments - immunology; Peptide Fragments - pharmacology; Peptides; Phosphorylation; Proteins; RNA; RNA, Small Interfering - genetics; RNA, Small Interfering - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; transcription (genetics); Transfection; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Wheat; Immunopathology; Nutrition; Peptides; Digestive system; Gut; Coeliac disease; Immunity; Signal transduction; Intestinal malabsorption; Gliadin; Digestive diseases; Intestinal disease; Enterocyte
• ISSN: 0002-9165; 1938-3207; 1938-3207
• DOI: 10.3945/ajcn.112.054544

Background: On ingestion of gliadin, the major protein component of wheat and other cereals, the celiac intestine is characterized by the proliferation of crypt enterocytes with an inversion of the differentiation/proliferation program. Gliadins and A-gliadin peptide P31-43, in particular, act as growth factors for crypt enterocytes in patients with celiac disease (CD). The effects of gliadin on crypt enterocyte proliferation and activation of innate immunity are mediated by epidermal growth factors (EGFs) and innate immunity mediators [interleukin 15 (IL15)].Objective: The aim of this study was to determine the molecular basis of proliferation and innate immune response to gliadin peptides in enterocytes.Design: The CaCo-2 cell line was used to study EGF-, IL15-, and P31-43–induced proliferation. Silencing messenger RNAs and blocking EGF receptor and IL15 antibodies have been used to study proliferation in CaCo-2 cells and intestinal biopsy samples from patients with CD and control subjects.Results: In the CaCo-2 cell model, IL15 and EGF cooperated to induce proliferation in intestinal epithelial cells at both the transcriptional and posttranscriptional levels, and the respective receptors interacted to activate each other's signaling. In addition, the effects of the P31-43 peptide on CaCo-2 cell proliferation and downstream signaling were mediated by cooperation between EGF and IL15. The increased crypt enterocyte proliferation in intestinal biopsy samples from patients with CD was reduced by EGF receptor and IL15 blocking antibodies only when used in combination.Conclusions: EGF receptor/IL15R-α cooperation regulates intestinal epithelial cell proliferation induced by EGF, IL15, and the gliadin peptide P31-43. Increased proliferation of crypt enterocytes in the intestine of CD patients is mediated by EGF/IL15 cooperation.