Sites of action for future therapy: an adenosine-dependent mechanism by which aspirin retains its antiinflammatory activity in cyclooxygenase-2 and NFkappaB knockout mice.
The antiinflammatory action of aspirin is generally attributed to inhibition of cyclooxygenases 1 and 2, but additional mechanisms are at work. These include inhibition of NFkappaB translocation to the nucleus and the capacity of aspirin to promote accumulation of adenosine, a potent antiinflammatory autocoid. We tested these hypotheses in the murine air pouch model of acute inflammation in wild type mice and in cyclooxygenase 2 or NFkappaB knockouts. The antiinflammatory effects of aspirin, sodium salicylate and indomethacin did not correlate with inhibition of cyclooxygenase in either group. Indeed, aspirin retained its antiinflammatory properties even in COX-2 knockouts. Similarly, aspirin was no less antiinflammatory in mice rendered deficient for NFkappaB (p105) than in wild type controls. In contrast, dexamethasone lost its antiinflammatory capacity in NFkappaB knockouts. Aspirin and sodium salicylate dramatically increased concentrations of adenosine in exudates, a property shared with methotrexate and sulfasalazine. Removal of adenosine by adenosine deaminase or specific antagonism of adenosine at A(2)receptors completely reversed the antiinflammatory effects of aspirin and sodium salicylate, but not those of dexamethasone. This adenosine-dependent, antiinflammatory effect of aspirin points to another target of drug development.
Department of Medicine, Division of Rheumatology, New York University School of Medicine, 550 First Ave., New York, NY, 10016, USA. cronsb01@mcrcr6.med.nyu.edu
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Cronstein
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Montesinos
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013805:Theobromine / Q000031:analogs & derivatives / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; C057837:3,7-dimethyl-1-propargylxanthine; D013805:Theobromine; D001241:Aspirin