title: Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease.
abstract: OBJECTIVE
  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: Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville 22908, USA.
authors: Masaru
authors: M
authors: Odashima
authors: Giorgos
authors: G
authors: Bamias
authors: Jesus
authors: J
authors: Rivera-Nieves
authors: Joel
authors: J
authors: Linden
authors: Cynthia C
authors: CC
authors: Nast
authors: Christopher A
authors: CA
authors: Moskaluk
authors: Marco
authors: M
authors: Marini
authors: Kazuhiko
authors: K
authors: Sugawara
authors: Kosuke
authors: K
authors: Kozaiwa
authors: Michiro
authors: M
authors: Otaka
authors: Sumio
authors: S
authors: Watanabe
authors: Fabio
authors: F
authors: Cominelli
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D003092:Colitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005557:Formaldehyde; D007079:Ileitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011687:Purines / Q000494:pharmacology*; D011817:Rabbits; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D012008:Recurrence
chemical_list: C431129:ATL 146e; D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines; D011687:Purines; D043705:Receptor, Adenosine A2A; D005557:Formaldehyde