Reduced cadherin/catenin complex expression in celiac disease can be reproduced in vitro by cytokine stimulation

Celiac disease is characterized by a chronic immune response to dietary glu ten, in which T cell responses result in elevated mucosal levels of tumor n ecrosis factor (TNF)-alpha, interleukin (IL)-1, interferon (IFN)-gamma, and transforming growth factor (TGF)-beta, which induce profound mucosal remod eling associated with increased enterocyte proliferation, apoptosis, and mi gration. Reduced intestinal expression of the morphoregulatory cell adhesio n molecule E-cadherin, which forms complexes with beta-catenin, can increas e enterocyte proliferation and migration. However, its mechanism of action in gastrointestinal inflammatory conditions and any involvement in celiac d isease is unknown. In this study, we describe changes in E-cadherin and bet a-catenin expression in celiac disease tissue and determine the effect of c ytokines on their expression in an in vitro model. We assessed E-cadherin a nd beta-catenin expression in intestinal biopsies from 24 patients with cel iac disease, 12 patients with treated celiac disease, and 10 healthy patien ts by immunohistochemistry, Western blotting, and confocal microscopy. Usin g Caco-2 cells, we examined the effect of TNF-alpha, IL-1, IFN-gamma, and T GF-beta on E-cadherin expression. E-cadherin transcription was assessed in both intestinal biopsies and Caco-2 cells by in situ hybridization and RT-P CR, respectively. A marked reduction in protein expression of E-cadherin an d beta-catenin that returns to normal levels after treatment was observed i n celiac disease; this reduction was associated with reduced levels of E-ca dherin mRNA. E-cadherin expression in Caco-2 cells was significantly reduce d after TNF-alpha, IL-1, and IFN-gamma stimulation. The effect of TNF-alpha on E-cadherin expression was maximal after stimulation for 48 hours and al so induced modest reductions in beta-catenin expression. The action of TNF- alpha on E-cadherin was reversible and was shown to act at the transcriptio nal level. These results demonstrate the novel findings that E-cadherin and beta-catenin expression are reversibly down-regulated in celiac disease an d that such changes in epithelial cadherin/catenin complexes may be mediate d by cytokines acting on cadherin transcription.