Transglutaminase 2 (tissue transglutaminase, TGase 2) was recently identified as an endomysial autoantigen in celiac disease (CD). Identification of how TGase 2 expression is increased may allow a better understanding of this autoimmune disease. Certain inflammatory cytokines, tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), and the Th type I cytokine interferon-γ (INF-γ) are abundant in CD. We have investigated whether these play a role in the regulation of TGase 2 expression in a model rat small intestinal epithelial cell line (IEC-6). After treatment for 24 h, TNF-α did not significantly alter TGase 2 mRNA or activity, but TGF-β decreased mRNA and activity by 4-5-fold. IFN-γ increased mRNA and TGase 2 activity by about 2-fold in 24 h and 5-fold by 5 days. Our new data suggest that increased TGase 2 expression in the upper small intestine of CD patients may be due to increased IFN-γ expression, loss of TGF-β signaling, or both.