Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease

Masaru Odashima, Giorgos Bamias, Jesus Rivera-Nieves, Joel Linden, Cynthia C. Nast, Christopher A. Moskaluk, Marco Marini, Kazuhiko Sugawara, Kosuke Kozaiwa, Michiro Otaka, Sumio Watanabe, Fabio Cominelli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

186 Scopus citations

Abstract

Background & Aims: Adenosine has been implicated as an important regulator of the inflammatory response. Four subtypes of adenosine receptors (A1, A2A, A2B, and A3) have been described, of which A2A potentially inhibits inflammation. The aim of this study was to investigate the role of A2A in mucosal inflammation by administering a selective A2A agonist (ATL-146e) to experimental models of inflammatory bowel disease. Methods: 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. Results: 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). Conclusions: A2A 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 A2A by selective agonism may therefore serve as a novel therapy for the treatment of inflammatory bowel disease.

Original languageEnglish
Pages (from-to)26-33
Number of pages8
JournalGastroenterology
Volume129
Issue number1
DOIs
StatePublished - Jul 2005
Externally publishedYes

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