ENDOGENOUS ADENOSINE CURTAILS LIPOPOLYSACCHARIDE-STIMULATED TUMOR-NECROSIS-FACTOR SYNTHESIS

Recent studies have demonstrated the inhibitory effect of exogenous ad enosine on TNF production. During inflammation endogenous adenosine le vels are elevated and may be one of several antiinflammatory mediators that reduce TNF synthesis. In the present study the authors investiga ted this role of adenosine in freshly isolated human PBMC. The effect of endogenous adenosine on TNF formation was studied by four different approaches. First, adenosine deaminase was added to LPS-stimulated mo nonuclear cells. This enzyme specifically deaminates extracellular ade nosine to the inactive metabolite inosine, TNF production was augmente d from baseline stimulation (LPS alone) of 3.5 +/- 0.4 ng ml(-1) - 5.2 +/- 0.4 ng ml(-1) in the presence of 10 U ml(-1) adenosine deaminase. Second, TNF production was determined after stimulation in the presen ce of dipyridamole, an inhibitor of cellular re-uptake of adenosine wh ich increases extracellular concentrations. TNF synthesis was reduced dose-dependently from 3.1 +/- 0.9 ng ml(-1) - 1.1 +/- 0.2 ng ml(-1) by 10 mu M dipyridamole. Third, the adenosine A(2) receptor antagonist 8 -(3-chlorostyryl)caffeine (100 nM) enhanced TNF synthesis from a basel ine of 3.7 +/- 0.5 ng ml(-1) - 5.5 +/- 0.9 ng ml(-1). In contrast, no increase resulted from the addition of 100 nM of the specific A(1) rec eptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. Finally, the auth ors were able to show that suppression of TNF formation by the specifi c type IV phosphodiesterase inhibitor rolipram can be completely rever sed by adenosine deaminase or by the application of the A(2) receptor antagonist. The authors conclude that endogenous adenosine controls TN F production. This effect of adenosine may not only have a physiologic al role but also appears to contribute to the pharmacological inhibiti on of TNF synthesis by exogenous agents such as the specific type IV p hosphodiesterase inhibitor rolipram.