Salicylates and sulfasalazine, but not glucocorticoids, inhibit leukocrte accumulation by an adenosine-dependent mechanism that is independent of inhibition of prostaglandin synthesis and p105 of NF#kappa#B

摘要

The antiinflammatory action of aspirin gen- erally has been attributed to direct inhibition of cyclooxyge- nases (COX-l and COX-2), but additional mechanisms are likely at work. These include aspirin's inhibition of NF#kappa#B translocation to the nucleus as well as the capacity of salicy- lates to uncouple oxidative phosphorylation (i.e., deplete ATP). At clinically relevant doses, salicylates cause cells to release micromolar concentrations of adenosine. which serves as an endogenous ligand for at least four different types of well-characterized receptors. Previously, we have shown that adenosine mediatcs the antiinflammatory effects of other potent and widely used antiinflammatory agents, methotrex- ate and sulfasalazine, both in vitro and in vivo. To determine in vivo whether clinically relevant levels of salicylate act via adenosine, via NF#kappa#B, or via the "inflammatory" cyclooxygen- ase COX-2, we studied acute inflammation in the generic murine air-pouch model by using wild-type mice and mice rendered deficient in either COX-2 or pl05, the precursor of p50, one of the components of the multimeric transcription factor NF#kappa#B. Here, we show that the antiinflammatory effects of aspirin and sodium salicylate, but not glucocorticoids, are largely mediated by the antiinflammatory autacoid adenosine independently of inhibition of prostaglandin synthesis by COX-1 or COX-2 or of the presence of pl05. Indeed, both inflammation and the antiinflammatory effects of aspirin and sodium salicylate were independent of the levels of prosta- glandins at the inflammatory site. T