Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study

Tiina Rauhavirta, Mikko Oittinen, Rami Kivistö, Pekka T. Männistö, J. Arturo Garcia-Horsman, Zhuo Wang, Martin Griffin, Markku Mäki, Katri Kaukinen, Katri Lindfors*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

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 celiacpatient- 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 Tcells (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 cellimpermeableR281seemedslightlymorepotent. Inaddition,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.

Original languageEnglish
Pages (from-to)134-142
Number of pages9
JournalJournal of Clinical Immunology
Volume33
Issue number1
Early online date10 Aug 2012
DOIs
Publication statusPublished - Jan 2013

Keywords

  • celiac disease
  • gliadin
  • small intestine
  • transglutaminase 2 inhibitor

Fingerprint Dive into the research topics of 'Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study'. Together they form a unique fingerprint.

  • Cite this

    Rauhavirta, T., Oittinen, M., Kivistö, R., Männistö, P. T., Garcia-Horsman, J. A., Wang, Z., Griffin, M., Mäki, M., Kaukinen, K., & Lindfors, K. (2013). Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study. Journal of Clinical Immunology, 33(1), 134-142. https://doi.org/10.1007/s10875-012-9745-5