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

Abstract

BACKGROUND & AIMS:

Adenosine has been implicated as an important regulator of the inflammatory response. Four subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) 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.

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 gamma, 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:

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.

• Authors: 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
• Journal: Gastroenterology (Gastroenterology) Vol. 129 Issue 1 Pg. 26-33 (Jul 2005) ISSN: 0016-5085 [Print] United States
• PMID: 16012931 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATL 146e
• Cyclohexanecarboxylic Acids
• Cytokines
• Purines
• Receptor, Adenosine A2A
• Formaldehyde

Topics

• Acute Disease
• Adoptive Transfer
• Animals
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• Chronic Disease
• Colitis (drug therapy, immunology, metabolism)
• Cyclohexanecarboxylic Acids (pharmacology)
• Cytokines (metabolism)
• Disease Models, Animal
• Formaldehyde
• Ileitis (drug therapy, immunology, metabolism)
• Inflammatory Bowel Diseases (drug therapy, immunology, metabolism)
• Male
• Mice
• Mice, SCID
• Purines (pharmacology)
• Rabbits
• Receptor, Adenosine A2A (metabolism)
• Recurrence