Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease.
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.
Odashima
Masaru
M
Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville 22908, USA.
Bamias
Giorgos
G
Rivera-Nieves
Jesus
J
Linden
Joel
J
Nast
Cynthia C
CC
Moskaluk
Christopher A
CA
Marini
Marco
M
Sugawara
Kazuhiko
K
Kozaiwa
Kosuke
K
Otaka
Michiro
M
Watanabe
Sumio
S
Cominelli
Fabio
F
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
C431129:ATL 146e; D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines; D011687:Purines; D043705:Receptor, Adenosine A2A; D005557:Formaldehyde