gamma-glutamylvaline and Colitis

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 γ-glutamyl dipeptides γ-glutamyl cysteine (γ-EC) and γ-glutamyl valine (γ-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 γ-EC and γ-EV in vitro in intestinal epithelial cells and in a mouse model of intestinal inflammation.. In vitro, treatment of Caco-2 cells with γ-EC and γ-EV resulted in the CaSR-mediated reduction of TNF-α-stimulated pro-inflammatory cytokines and chemokines including IL-8, IL-6, and IL-1β, and inhibited phosphorylation of JNK and IκBα, while increasing expression of IL-10. In vivo, using a mouse model of dextran sodium sulfate (DSS)-induced colitis, γ-EC and γ-EV treatment ameliorated DSS-induced clinical signs, weight loss, colon shortening and histological damage. Moreover, γ-EC and γ-EV reduced the expression of TNF-α, IL-6, INF-γ, IL-1β, 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 γ-EC were abrogated in β-arrestin2 knock-down Caco-2 cells, and involvement of β-arrestin2 was found to inhibit TNF-α-dependent signaling via cross-talk with the TNF-α receptor (TNFR).. Thus CaSR activation by γ-EC and γ-EV can aid in maintaining intestinal homeostasis and reducing inflammation in chronic inflammatory conditions such as IBD.

Topics: Allosteric Regulation; Animals; Arrestins; beta-Arrestins; Blotting, Western; Caco-2 Cells; Colitis; Cytokines; Dextran Sulfate; Dipeptides; Epithelial Cells; Female; Humans; Inflammation Mediators; Intestines; JNK Mitogen-Activated Protein Kinases; Mice, Inbred BALB C; Phosphorylation; Receptors, Calcium-Sensing; Receptors, Tumor Necrosis Factor; RNA Interference; Signal Transduction; Tumor Necrosis Factor-alpha