HUMAN MONONUCLEAR PHAGOCYTES EXPRESS ADENOSINE-A1-RECEPTORS - A NOVELMECHANISM FOR DIFFERENTIAL REGULATION OF FC-GAMMA RECEPTOR FUNCTION

Using monoclonal anti-adenosine A1 receptor antibodies that bind the A 1 receptor ligand binding site, we demonstrate that A1 receptors are e xpressed on cultured monocytes and rheumatoid synovial fluid mononucle ar phagocytes. This finding is associated with the acquisition of reac tivity with selective adenosine A1 receptor agonists and is temporally coordinated with the induction of adenosine A2 receptors on cultured monocytes. In a rapid, concentration-dependent fashion, these two dist inct adenosine receptors modulate Fcgamma receptor-mediated phagocytos is, a response critical to the pathogenesis of immune complex diseases . Occupancy of A1 receptors by N6-cyckopentyladenosine (an A1-specific adenosine analogue) or mAb AA1 (an anti-A1 mAb) results in a potent s timulation that is blocked by adenosine receptor antagonists. This A1 receptor-induced enhancement of Fcgamma receptor-mediated phagocytosis is a consequence of preferential augmentation of FcgammaRI function, suggesting distinct mechanisms for receptor-effector coupling of Fcgam ma receptor families. In contrast, ligation of A2 receptors by A2-spec ific agonists decreases Fcgamma receptor-mediated phagocytosis in cult ured monocytes. The opposing effects of adenosine A1 and A2 receptors allow for a concentration-dependent feed-back loop that responds more rapidly than effects elicited by other endogenous modulators. Low conc entrations of adenosine are proinflammatory providing enhanced Fc-gamm a receptor function via A1 receptors, whereas higher concentrations th at can occur with tissue damage are anti-inflammatory providing inhibi tion via A2 receptors. This rapid and potent modulation of Fcgamma rec eptor-mediated function suggests that adenosine is an important local regulator of the inflammatory response.