Adenosine is a potent endogenous antiinflammatory agent released by cells under metabolically unfavorable conditions. Its effects on the production of IL-10 by human monocytes were presently investigated. Pre-incubation with adenosine dose-dependently enhanced IL-10 release by TNF stimulated human monocytes (+29, +58, and +116% at 1, 10, and 100 muM, respectively.) Adenosine also significantly enhanced IL-10 production after hydrogen peroxide and LPS stimulation and dose-dependently inhibited TNF secretion. Pre-incubation was not mandatory to achieve these effects, since addition of adenosine at the time of or 30 min after the stimulus led to the same results. Blocking IL-10 with anti-IL-10 mAbs partially restored adenosine-induced TNF inhibition. The enhanced IL-10 production was not observed when cells were preincubated with adenosine A1 or A2 receptor agonists (R-phenylisopropyladenosine, 5'-N-ethylcarboxamido-adenosine, and 2-chloroadenosine) and was not affected by pretreatment with theophyllin, an antagonist of both A1 and A2 receptors, or with dipyridamole, an inhibitor of adenosine cellular uptake. In conclusion, adenosine, in the submillimolar concentration range, increases IL-10 secretion by stimulated monocytes. This phenomenon participates in TNF inhibition, a known property of adenosine, but is not mediated through the occupancy of A1 or A2 receptors. This may represent a novel antiinflammatory property of adenosine by which it could modulate inflammation and limit ischemia-reperfusion injury.