Are Transglutaminase 2 Inhibitors Able to Reduce Gliadin-Induced Toxicity Related to Celiac Disease? A Proof-of-Concept Study
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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.
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.
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.
Our results suggest that TG2 inhibitors are able to reduce certain gliadin-induced effects related to responses in vitro and ex vivo.
KeywordsCeliac disease gliadin transglutaminase 2 inhibitor small intestine
The Celiac Disease Study Group has been financially supported by the Academy of Finland, the SalWe Research Program for Intelligent Monitoring of Health and Wellbeing (Tekes—the Finnish Funding Agency for Technology and Innovation grant 648/10), the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, the Sigrid Juselius Foundation, the Competitive Research Funding of Tampere University Hospital, the Research Fund of the Finnish Celiac Society, the European Commission IAPP grant TRANSCOM (Contract number PIA-GA-2010-251506) and Elna Kaarina Savolainen’s Legacy Allocated for the Development of Cancer Treatment.
Conflict of interest
The authors declare no conflict of interest.
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