Differential requirement for A2a and A3 adenosine receptors for the protective effect of inosine in vivo.
Inosine is an endogenous nucleoside with immunosuppressive properties that is known to inhibit the accumulation of proinflammatory cytokines and protect mice from endotoxin-induced inflammation and lung tissue damage. There are no known receptors specific for inosine, but A3 adenosine receptors (A3Rs) have been shown to bind inosine, resulting in mast cell degranulation and increased vascular permeability. The present study specifically addresses the requirement for A2aR and/or A3R for the protective effect of inosine in 2 experimental in vivo models of inflammatory disease. The data show that A3R is essential for protection against ConA-induced fulminant hepatitis since only A3R-expressing mice were protected by inosine whereas wild-type and A2aR-deficient mice exhibited severe liver damage even after administration of inosine. In addition, we show in a model of LPS-induced endotoxemia that inosine protected both A2aR-/- and A3R-/- mice from inflammation, but not A2aA3R double-null mice, indicating that in this model both A2aR and A3R were used by inosine. Thus, we demonstrate that A2a and A3 adenosine receptors are differentially utilized by inosine for the down-regulation of tissue damage under different inflammatory conditions in vivo.
Gomez
Gregorio
G
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10/11N311, 10 Center Dr-MSC 1892, Bethesda, MD 20892-1892, USA.
Sitkovsky
Michail V
MV
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003208:Concanavalin A / Q000633:toxicity; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy* / Q000276:immunology; D022781:Hepatocytes / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007288:Inosine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D043684:Receptor, Adenosine A3 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007288:Inosine; D000410:Alanine Transaminase