Adenosine has been implicated as an important regulator of the inflammatory response. Four subtypes of adenosine receptors (A₁, A_2A, A_2B, and A₃) have been described, of which A_2A potentially inhibits inflammation. The aim of this study was to investigate the role of A_2A in mucosal inflammation by administering a selective A_2A agonist (ATL-146e) to experimental models of inflammatory bowel disease.

The anti-inflammatory effects of ATL-146e were studied in the acute and chronic rabbit formalin-immune complex models of colitis and the SAMP1/YitFc mouse model of spontaneous ileitis.

ATL-146e significantly reduced the acute inflammatory index and tissue necrosis compared with vehicle (P < .01) in the acute model of rabbit immune colitis. In the chronic rabbit immune colitis model, ATL-146e significantly suppressed inflammatory cell infiltration into the colonic mucosa (P < .05) and prevented mortality. The administration of ATL-146e significantly decreased the chronic inflammatory index (P < .01) and villus distortion index (P < .01) in the ileum of SAMP1/YitFc mice, and ameliorated adoptively transferred ileitis in severe combined immunodeficient mice injected with CD4⁺ T cells from SAMP1/Yit mice (P < .05). Tumor necrosis factor, interferon γ, and interleukin 4 concentrations were significantly suppressed by ATL-146e treatment in supernatants from cultures of mesenteric lymph node cells of SAMP1/YitFc mice (P < .05 vs vehicle-treated mice).

A_2A adenosine receptor activation by ATL-146e significantly reduced inflammation in the intestinal mucosa. This effect was associated with decreased leukocyte infiltration and inhibition of proinflammatory cytokines. Activation of A_2A by selective agonism may therefore serve as a novel therapy for the treatment of inflammatory bowel disease.