摘要：

The adenosine A2 receptors are known to mediate most of the anti-inflammatory activities of adenosine. In lipopolysaccharides (LPS)-stimulated macrophages adenosine strongly inhibits TNF-α release, but may also enhance PGE2 generation. The aims of this study were to determine the relative contributions of the A2A and A2B receptor subclasses in these two effects and to determine whether the enhanced release of PGE2 contributes to the inhibition of TNF-α release. In LPS-stimulated mouse macrophages, adenosine potently inhibited TNF-α production and also potentiated PGE2 release, though less potently (IC50 = 250 nM vs EC50 ≈ 8 μM, respectively). The non-selective adenosine receptor agonist NECA, and the selective A2A receptor agonist CGS21680 also inhibited TNF-α production even more potently (IC50 = 4.8 and 2.3 nM, respectively). NECA, but not CGS21680, also enhanced PGE2 production. The selective A2A receptor antagonist ZM241385 (30 nM), but not the selective A2B receptor antagonist MRS1754 (30 nM), blocked the inhibitory effect of NECA and CGS21680 on TNF-α release. On the other hand, MRS1754, but not ZM241385, abolished the PGE2 potentiating effect of NECA. Pre-treatment with indomethacin (1 μM) abolished adenosine-induced PGE2 release enhancement but did not prevent the inhibition of TNF-α release. These results show that in this system, the inhibition of TNF-α release by adenosine is mediated by the A2A receptors whereas the enhancement of PGE2 release appears to be mediated by the A2B receptors. The results also show that while exogenous PGE2 is a potent inhibitor of TNF-α release, the enhanced PGE2 release induced by adenosine does not appear to contribute to the inhibition of TNF-α release.

展开