| First Author | Zhang H | Year | 2015 |
| Journal | Biochim Biophys Acta | Volume | 1852 |
| Issue | 5 | Pages | 792-804 |
| PubMed ID | 25558818 | Mgi Jnum | J:234455 |
| Mgi Id | MGI:5790032 | Doi | 10.1016/j.bbadis.2014.12.023 |
| Citation | Zhang H, et al. (2015) gamma-Glutamyl cysteine and gamma-glutamyl valine inhibit TNF-alpha signaling in intestinal epithelial cells and reduce inflammation in a mouse model of colitis via allosteric activation of the calcium-sensing receptor. Biochim Biophys Acta 1852(5):792-804 |
| abstractText | BACKGROUND: The extracellular calcium-sensing receptor (CaSR) is distributed throughout the gastrointestinal tract, and its activation has been shown to promote intestinal homeostasis, suggesting that CaSR may be a promising target for novel therapies to prevent chronic intestinal inflammation such as inflammatory bowel disease (IBD). The gamma-glutamyl dipeptides gamma-glutamyl cysteine (gamma-EC) and gamma-glutamyl valine (gamma-EV) are dietary flavor enhancing compounds, and have been shown to activate CaSR via allosteric ligand binding. The aim of this study was to examine the anti-inflammatory effects of gamma-EC and gamma-EV in vitro in intestinal epithelial cells and in a mouse model of intestinal inflammation. RESULTS: In vitro, treatment of Caco-2 cells with gamma-EC and gamma-EV resulted in the CaSR-mediated reduction of TNF-alpha-stimulated pro-inflammatory cytokines and chemokines including IL-8, IL-6, and IL-1beta, and inhibited phosphorylation of JNK and IkappaBalpha, while increasing expression of IL-10. In vivo, using a mouse model of dextran sodium sulfate (DSS)-induced colitis, gamma-EC and gamma-EV treatment ameliorated DSS-induced clinical signs, weight loss, colon shortening and histological damage. Moreover, gamma-EC and gamma-EV reduced the expression of TNF-alpha, IL-6, INF-gamma, IL-1beta, and IL-17, and increased the expression of IL-10 in the colon, in a CaSR-dependent manner. The CaSR-mediated anti-inflammatory effects of gamma-EC were abrogated in beta-arrestin2 knock-down Caco-2 cells, and involvement of beta-arrestin2 was found to inhibit TNF-alpha-dependent signaling via cross-talk with the TNF-alpha receptor (TNFR). CONCLUSIONS: Thus CaSR activation by gamma-EC and gamma-EV can aid in maintaining intestinal homeostasis and reducing inflammation in chronic inflammatory conditions such as IBD. |
