Blockade of adenosine A2B 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.