Signalling pathways controlling the TG2 expression in the small intestinal mucosa

BAYARDO, MARIELA; BONDAR, CONSTANZA; CHIRDO, FERNANDO

Encuentro; Proceedings of the 24th meeting of Working Group on Prolamin Analysis and Toxicity; 2010

Transglutaminase 2 (TG2) is a multifunctional protein located in several cell compartments. TG2 works as a G protein in transmembrane signalling and has protein disulphide isomerase and protein kinase activity. It is, however, the catalytic activity leading to either deamidation or formation of e-(g-glutamil) lysine crosslinks between proteins (termed transamidation) that has received major attention. Its functional properties have important roles in tissue repair, inflammation and apoptosis. The dysregulation of TG2 is involved in the pathogenesis of various human disorders, including neurodegenerative and autoimmune diseases. Particularly in coeliac disease (CD), selective deamidation of glutamine residues in gliadin/glutenin-derived peptides leads to higher affinity binding to the HLA predisposing alleles leading to greater gliadin-specific T cell stimulation. The aim of this study was to evaluate the induction of TG2 expression by proinflammatory cytokines and to assess the signalling pathways operating in the small intestine. Different proinflammatory cytokines were used to modulate the expression of TG2 in an in-vitro model of human enterocytes (Caco-2 cells). Among the cytokines tested, gIFN was the most potent inducer of TG2 expression. A synergistic effect on the expression of TG2 was observed in cells stimulated with a combination of TNFa+ gIFN. Similar results were also observed when intestinal biopsies were treated with these cytokines. Since TNFa and gIFN are present in the small intestine in untreated CD patients, the higher induction of TG2 by these cytokines must be considered as part of the pathogenic mechanism in CD. Specific inhibitors selectively blocked signalling pathways involved in the induction of TG2 by TNFa and gIFN. These effects were also observed in biopsy samples of the small intestine mucosa. Since signals producing upregulation of TG2 can participate in several disease processes and particularly in CD, the knowledge of the molecular pathways triggering the induction of TG2 constitutes valuable information for the development of new therapeutic approaches