title: An undigested gliadin peptide activates innate immunity and proliferative signaling in enterocytes: the role in celiac disease.
abstract: 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.
  
  
  METHODS
  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.
authors: Department of Pediatrics and European Laboratory for the Investigation of Food Induced Disease, University of Naples, Federico II, Naples, Italy, and the Department of Medicine, University of Chicago, Chicago, IL.
authors: Merlin
authors: M
authors: Nanayakkara
authors: Giuliana
authors: G
authors: Lania
authors: Mariantonia
authors: M
authors: Maglio
authors: Valentina
authors: V
authors: Discepolo
authors: Marco
authors: M
authors: Sarno
authors: Alessandra
authors: A
authors: Gaito
authors: Riccardo
authors: R
authors: Troncone
authors: Salvatore
authors: S
authors: Auricchio
authors: Renata
authors: R
authors: Auricchio
authors: Maria Vittoria
authors: MV
authors: Barone
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D018938:Caco-2 Cells; D002446:Celiac Disease / Q000276:immunology* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020895:Enterocytes / Q000276:immunology* / Q000473:pathology*; D004815:Epidermal Growth Factor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D005903:Gliadin / Q000276:immunology* / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate; D019409:Interleukin-15 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D053720:Interleukin-15 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection
chemical_list: D000906:Antibodies; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C549457:gliadin p31-43; D004815:Epidermal Growth Factor; D005903:Gliadin; D066246:ErbB Receptors