title: Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study.
abstract: OBJECTIVE
  Celiac disease is an autoimmune-mediated enteropathy characterized by adaptive and innate immune responses to dietary gluten in wheat, rye and barley in genetically susceptible individuals. Gluten-derived gliadin peptides are deamidated by transglutaminase 2 (TG2), leading to an immune response in the small-intestinal mucosa. TG2 inhibitors have therefore been suggested as putative drugs for celiac disease. In this proof-of-concept study we investigated whether two TG2 inhibitors, cell-impermeable R281 and cell-permeable R283, can prevent the toxic effects of gliadin in vitro and ex vivo.
  
  
  METHODS
  Intestinal epithelial Caco-2 cells were treated with peptic-tryptic-digested gliadin (PT-gliadin) with or without TG2 inhibitors and thereafter direct toxic effects (transepithelial resistance, cytoskeletal rearrangement, junction protein expression and phoshorylation of extracellular-signal-regulated kinase 1/2) were determined. In an organ culture of celiac-patient-derived small-intestinal biopsies we measured secretion of TG2-autoantibodies into the culture medium and the densities of CD25- and interleukin (IL) 15-positive cells, forkhead box P3 (FOXP3)-positive regulatory T cells (Tregs) and Ki-67-positive proliferating crypt cells.
  
  
  RESULTS
  Both TG2 inhibitors evinced protective effects against gliadin-induced detrimental effects in Caco-2 cells but the cell-impermeable R281 seemed slightly more potent. In addition, TG2 inhibitor R281 modified the gluten-induced increase in CD25- and IL15-positive cells, Tregs and crypt cell proliferation, but had no effect on antibody secretion in celiac-patient-derived biopsies.
  
  
  CONCLUSIONS
  Our results suggest that TG2 inhibitors are able to reduce certain gliadin-induced effects related to responses in vitro and ex vivo.
authors.affiliation: Pediatric Research Center, University of Tampere and Tampere University Hospital, Tampere, 33014, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Rauhavirta
authors.forename: Mikko
authors.initials: M
authors.lastname: Oittinen
authors.forename: Rami
authors.initials: R
authors.lastname: Kivistö
authors.forename: Pekka T
authors.initials: PT
authors.lastname: Männistö
authors.forename: J Arturo
authors.initials: JA
authors.lastname: Garcia-Horsman
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.forename: Martin
authors.initials: M
authors.lastname: Griffin
authors.forename: Markku
authors.initials: M
authors.lastname: Mäki
authors.forename: Katri
authors.initials: K
authors.lastname: Kaukinen
authors.forename: Katri
authors.initials: K
authors.lastname: Lindfors
mesh_terms: D018938:Caco-2 Cells; D002446:Celiac Disease / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005903:Gliadin / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D005983:Glutens / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D009924:Organ Culture Techniques; D010865:Pilot Projects; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D005983:Glutens; D005903:Gliadin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins