TG2 expression is synergistically enhanced by IFNg; and TNFa in human small intestine

BAYARDO M; PUNZI F; BONDAR C; CHOPITA N; CHIRDO F.G

CLINICAL AND EXPERIMENTAL IMMUNOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2012 vol. 168 p. 95 - 104

0009-9104

Transglutaminase 2 (TG2) is ubiquitously expressed, has multiple physiological functions and has also been associated with inflammatory diseases, neurodegenerative disorders, autoimmunity and cancer. Particularly, TG2 is expressed in small intestine mucosa where it is upregulated in active Coeliac Disease (CD). The aim of this work was to investigate the induction of TG2 expression by proinflammatory cytokines (IL-1, IL-6, TNFα, IFNγ and IL-15) and the signalling pathways involved, in human epithelial and monocytic cells and in intestinal tissue from controls and untreated coeliac disease patients. Here we report that IFNγ was the most potent inducer of TG2 expression in the small intestinal mucosa and in four (Caco-2, HT-29, Calu-6 and THP-1) out of five cell lines tested. Combination of TNFα and IFNγ produced a strong synergistic effect. The use of selective inhibitors of signalling pathways unveiled that induction of TG2 by IFNγ was mediated by PI3K, while JNK and p38MAPK were required for TNFα activation. Quantitative PCR, flow cytometry and western-blot analysis showed that TG2 expression was completely blocked when stimulation by either TNFα or IFNγ was performed in the presence of NF-κB inhibitors (Sulfasalazine and BAY-117082). TG2 was substantially upregulated by TNFα and IFNγ in intestinal mucosa in untreated Coeliac Disease compared with controls. NF-κB activation was required for TG2 induction in intestinal tissue. This study shows that IFNγ, a dominant cytokine in intestinal mucosa in active CD, is the most potent inducer of TG2, and synergism with TNFα may contribute to exacerbate the pathogenic mechanism of CD. Selective inhibition of signalling pathways may be of therapeutic benefit.