Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study
Rauhavirta, Tiina; Oittinen, Mikko; Kivistö, Rami; Männistö, Pekka T.; Garcia-Horsman, J. Arturo; Wang, Zhuo; Griffin, Martin; Mäki, Markku; Kaukinen, Katri and Lindfors, Katri (2012). Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study. Journal of clinical immunology, Online first ,
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Official URL: http://www.springerlink.com/content/12438n24570427...
Purpose: 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.
|Additional Information:||Copyright 2012 Elsevier B.V., All rights reserved.|
|Uncontrolled Keywords:||celiac disease, small intestine, transglutaminase 2 inhibitor, gliadin|
|Divisions:||Schools_of_Study > Life & Health Sciences > Biosciences (LHS)|
Support_Departments > Senior Pro-Vice-Chancellor > PVC (Research) > PVC's Office (Res)
|Deposited By:||Prof Alfred Admin|
|Deposited On:||11 Dec 2012 13:51|
|Last Modified:||10 Dec 2013 08:33|
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