Human mononuclear phagocytes express adenosine A1 receptors. A novel mechanism for differential regulation of Fc gamma receptor function.
Using monoclonal anti-adenosine A1 receptor antibodies that bind the A1 receptor ligand binding site, we demonstrate that A1 receptors are expressed on cultured monocytes and rheumatoid synovial fluid mononuclear phagocytes. This finding is associated with the acquisition of reactivity 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 distinct adenosine receptors modulate Fc gamma receptor-mediated phagocytosis, a response critical to the pathogenesis of immune complex diseases. Occupancy of A1 receptors by N6-cyclopentyladenosine (an A1-specific adenosine analogue) or mAb AA1 (an anti-A1 mAb) results in a potent stimulation that is blocked by adenosine receptor antagonists. This A1 receptor-induced enhancement of Fc gamma receptor-mediated phagocytosis is a consequence of preferential augmentation of Fc gamma RI function, suggesting distinct mechanisms for receptor-effector coupling of Fc gamma receptor families. In contrast, ligation of A2 receptors by A2-specific agonists decreases Fc gamma receptor-mediated phagocytosis in cultured 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 concentrations of adenosine are proinflammatory providing enhanced Fc gamma receptor function via A1 receptors, whereas higher concentrations that can occur with tissue damage are anti-inflammatory providing inhibition via A2 receptors. This rapid and potent modulation of Fc gamma receptor-mediated function suggests that adenosine is an important local regulator of the inflammatory response.
Salmon
J E
JE
Department of Medicine, Hospital for Special Surgery, New York, NY 10021.
Brogle
N
N
Brownlie
C
C
Edberg
J C
JC
Kimberly
R P
RP
Chen
B X
BX
Erlanger
B F
BF
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D009000:Monocytes / Q000502:physiology; D009504:Neutrophils / Q000737:chemistry; D010586:Phagocytes / Q000737:chemistry / Q000502:physiology*; D010587:Phagocytosis; D017452:Receptors, IgG / Q000502:physiology*; D011983:Receptors, Purinergic / Q000032:analysis / Q000502:physiology*
D000911:Antibodies, Monoclonal; D017452:Receptors, IgG; D011983:Receptors, Purinergic; C048599:N(6)-cyclopentyladenosine; D000241:Adenosine