Activation of A2A Adenosine Receptor Attenuates Intestinal Inflammation in Animal Models of Inflammatory Bowel Disease

Gastroenterology. 2005 Jul;129(1):26-33. doi: 10.1053/j.gastro.2005.05.032.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

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