Transient Receptor Potential Vanilloid 4 Activated Inflammatory Signals by Intestinal Epithelial Cells and Colitis in Mice

BACKGROUND & AIMS: Ligand-gated calcium channels have been reported to be involved in the pathogenesis of inflammatory bowel disease. One family member, transient receptor potential vanilloid 4 (TRPV4), is activated by arachidonic acid derivatives that might be released on inflammation, yet its role in gastrointestinal inflammation has not been characterized. We investigated whether TRPV4 activation participates in intestinal inflammation and its expression and functions in the gastrointestinal tract. METHODS: TRPV4 expression was studied in human colon samples, human intestinal epithelial cell lines (Caco-2 and T84), and inflamed colons of mice. Calcium mobilization and cytokine release were analyzed in intestinal epithelial cells exposed to the selective TRPV4 agonist 4 alpha-phorbol-12,13-didecanoate (4 alpha PDD). Mice were killed 3, 6, or 24 hours after intracolonic administration of 4 alpha PDD; inflammatory parameters were measured in their colon tissues, and paracellular colonic permeability was measured by the passage of Cr-51-EDTA from the colon lumen to the blood. RESULTS: High levels of TRPV4 were detected in Caco-2 cells and in epithelial cells of human colon tissue samples; its expression was up-regulated in colons from inflamed mice compared with noninflamed control mice. Administration of 4 alpha PDD to Caco-2 and T84 cells caused a dose-dependent increase in intracellular calcium concentration and chemokine release. In mice, intracolonic administration of 4 alpha PDD caused colitis to develop 3 to 6 hours later; inflammation resolved by 24 hours. Increased colonic permeability was observed in vivo 3 hours after intracolonic administration of 4 alpha PDD. CONCLUSIONS: TRPV4 is expressed and functional in intestinal epithelial cells; its activation in the gastrointestinal tract causes increases in intracellular calcium concentrations, chemokine release, and colitis.