Salicylates and sulfasalazine, but not glucocorticoids, inhibit leukocyte accumulation by an adenosine-dependent mechanism that is independent of inhibition of prostaglandin synthesis and p105 of NFkB

The antiinf lammatory action of aspirin generally has been attributed to direct inhibition of cyclooxygenases (COX-1 and COX-2), but additional mechanisms are likely at work. These include aspirin’s inhibition of NFkB translocation to the nucleus as well as the capacity of salicylates 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 mediates the antiinf lammatory effects of other potent and widely used antiinf lammatory agents, methotrexate and sulfasalazine, both in vitro and in vivo. To determine in vivo whether clinically relevant levels of salicylate act via adenosine, via NFkB, or via the ‘‘inf lammatory’’ cyclooxygenase COX-2, we studied acute inf lammation in the generic murine air-pouch model by using wild-type mice and mice rendered deficient in either COX-2 or p105, the precursor of p50, one of the components of the multimeric transcription factor NFkB. Here, we show that the antiinf lammatory effects of aspirin and sodium salicylate, but not glucocorticoids, are largely mediated by the antiinf lammatory autacoid adenosine independently of inhibition of prostaglandin synthesis by COX-1 or COX-2 or of the presence of p105. Indeed, both inf lammation and the antiinf lammatory effects of aspirin and sodium salicylate were independent of the levels of prostaglandins at the inf lammatory site. These experiments also provide in vivo confirmation that the antiinf lammatory effects of glucocorticoids depend, in part, on the p105 component of