Ligand-activation of the adenosine A2a receptors inhibits IL-12 productionby human monocytes

Adenosine (ADO) exerts potent anti-inflammatory and immunosuppressive effec ts. In this paper we address the possibility that these effects are partly mediated by inhibition of the secretion of IL-12, a proinflammatory cytokin e and a major inducer of Th1 responses. We demonstrate that 5'-N-ethylcarbo xamidoadenosine (NECA), a nonspecific ADO analogue, and 2-p-(2-carbonylethy l)phenylethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680), a specific A 2a receptor agonist, dose-dependently inhibited, in whole blood ex vivo and monocyte cultures, the production of human IL-12 induced by LPS and Stapho lococcus aureus Cowan strain 1, However, the Al receptor agonist 2-Chloro-N -6-cyclopentyladenosine and the A3 receptor agonists N-6-Benzyl-NECA and 1- deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-yl]-N-methyl-beta-D-ribof uranuronamide expressed only weak inhibitory effects. On the other hand, NE CA and CGS-21680 dose-dependently potentiated the production of IL-10, The differential effect of these drugs on monocyte IL-12 and IL-10 production i mplies that these effects are mediated by A2a receptor signaling rather tha n by intracellular toxicity of ADO analogue's metabolites. Moreover, CGS-21 680 inhibited IL-12 production independently of endogenous IL-10 induction, because anti-IL-10 Abs failed to prevent its effect, The selective A2a ant agonist 8-(3-Chlorostyryl) caffeine prevented the inhibitory effect of CGS- 21680 on IL-12 production, The phosphodiesterase inhibitor Ro 20-1724 dose- dependently potentiated the inhibitory effect of CGS-21680 and, furthermore , Rp-cAMPS, a protein kinase A inhibitor, reversed the inhibitory effect of CGS-21680, implicating a cAMP/protein kinase A pathway in its action. Thus , ligand activation of A2a receptors simultaneously inhibits IL-12 and stim ulates IL-10 production by human monocytes, Through this mechanism, ADO rel eased in excess during inflammatory and ischemic conditions, or tissue inju ry, may contribute to selective suppression of Th1 responses and cellular i mmunity.