The antiinflammatory effects of methotrexate are mediated by adenosine.
In summary, intermittent, low dose methotrexate treatment is: 1.) antiinflammatory in the murine air pouch model of inflammation; 2.) selectively increases intracellular AICAR concentration; 3.) increases adenosine concentration in an inflammatory exudate; and, 4.) inhibits leukocyte accumulation at an inflamed site by a mechanism that is specifically reversed by adenosine deaminase and the adenosine A2 receptor antagonist DMPX but not the A1 antagonist DPCPX. In conclusion, we have demonstrated a novel mechanism for the antiinflammatory action of methotrexate; methotrexate is a nonsteroidal antiinflammatory agent that acts by promoting the release of adenosine which engages A2 receptors on inflammatory cells.
Cronstein
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Department of Medicine, New York University Medical Center, New York 10016, USA.
Naime
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Ostad
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D000217:Acyltransferases / Q000037:antagonists & inhibitors; D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000494:pharmacology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002351:Carrageenan; D019877:Hydroxymethyl and Formyl Transferases; D007249:Inflammation / Q000503:physiopathology*; D007700:Kinetics; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D058915:Purinergic P1 Receptor Antagonists; D012265:Ribonucleotides / Q000378:metabolism; D013805:Theobromine / Q000031:analogs & derivatives / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D058915:Purinergic P1 Receptor Antagonists; D012265:Ribonucleotides; D014970:Xanthines; D000620:Aminoimidazole Carboxamide; C057837:3,7-dimethyl-1-propargylxanthine; D002351:Carrageenan; C051360:1,3-dipropyl-8-cyclopentylxanthine; D019877:Hydroxymethyl and Formyl Transferases; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D000217:Acyltransferases; D000243:Adenosine Deaminase; C031143:AICA ribonucleotide; D000241:Adenosine; D013805:Theobromine; D008727:Methotrexate