Blockade of adenosine A _2B receptors ameliorates murine colitis

Background and purpose: The adenosine 2B (A _2B) receptor is the predominant adenosine receptor expressed in the colon. Acting through the A _2B receptor, adenosine mediates chloride secretion, as well as fibronectin and interleukin (IL)-6 synthesis and secretion in intestinal epithelial cells. A _2B receptor mRNA and protein expression are increased during human and murine colitis. However, the effect of the A _2B receptor in the activation of the intestinal inflammatory response is not known. In this study, we examined the effect of A _2B receptor antagonism on murine colitis. Experimental approach: Dextran sodium sulphate (DSS)-treated mice and piroxicam-treated IL-10 ^-/- mice were used as animal models of colitis. The A _2B receptor-selective antagonist, ATL-801, was given in the diet. Key results: Mice fed ATL-801 along with DSS showed a significantly lower extent and severity of colitis than mice treated with DSS alone, as shown by reduced clinical symptoms, histological scores, IL-6 levels and proliferation indices. The administration of ATL-801 prevented weight loss, suppressed the inflammatory infiltrate into colonic mucosa and decreased epithelial hyperplasia in piroxicam-treated IL-10 ^-/- mice. IL-6 and keratinocyte-derived chemokine (KC) concentrations in the supernatants of colonic organ cultures from colitic mice were significantly reduced by ATL-801 administration. Conclusions and implications: Taken together, these data demonstrate that the intestinal epithelial A _2B receptor is an important mediator of pro-inflammatory responses in the intestine and that A _2B receptor blockade may be an effective therapeutic strategy to treat inflammatory bowel disease.