Fc gamma receptor-mediated functions in neutrophils are modulated by adenosine receptor occupancy. A1 receptors are stimulatory and A2 receptors are inhibitory.
Adenosine, an endogenously released purine, modulates the functions of many cells through surface A1 and A2 receptors. We examined the hypothesis that adenosine receptor ligation regulates Fc gamma R-triggered inflammatory response by polymorphonuclear leukocytes (PMN), a response which is critical to the pathogenesis of immune complex diseases. The effects of adenosine analogs on Fc gamma R-mediated phagocytosis and superoxide anion (O2-) generation in human neutrophils were investigated. 5'(N-ethyl)carboxamidoadenosine (NECA), the most potent A2 receptor agonist, inhibited Fc gamma R-mediated phagocytosis and O2- generation, whereas N6-cyclopentyladenosine (CPA), a highly selective A1 receptor agonist, enhanced these functions. The effects of the adenosine analogs were markedly accentuated in neutrophils adherent to biologic surfaces. Both the inhibition by NECA and the enhancement by CPA of PMN Fc gamma R functions were blocked by the adenosine receptor antagonist 8-p-sulfophenyltheophylline, which suggests that occupancy of surface adenosine receptors mediated the actions of these analogs. Because A1 receptors on PMN are linked to pertussis toxin-sensitive G proteins, our evidence that pertussis toxin blocked the effects on Fc gamma R function brought about by CPA but not by NECA further supports the hypothesis that CPA acts via an A1 receptor. Our data indicate that adenosine A1 and A2 receptors modulate neutrophil Fc gamma R function in opposing ways, allowing for a concentration-dependent, adenosine-regulated feed-back loop. At low concentrations there is enhancement of neutrophil Fc gamma R function via PMN A1 receptors, whereas at higher concentrations (those which may occur at sites of damaged tissues), there is inhibition via A2 receptors. Our observation that adenosine analogs had more potent effects on adherent neutrophils emphasizes the potential importance of adenosine as a modulator of Fc gamma R-triggered inflammation in vivo.
Salmon
J E
JE
Department of Medicine, Hospital for Special Surgery, New York, NY 10021.
Cronstein
B N
BN
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000943:Antigens, Differentiation / Q000502:physiology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D009504:Neutrophils / Q000502:physiology*; D037342:Pertussis Toxin; D010587:Phagocytosis; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D011961:Receptors, Fc / Q000502:physiology*; D017452:Receptors, IgG; D011983:Receptors, Purinergic / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000943:Antigens, Differentiation; D011961:Receptors, Fc; D017452:Receptors, IgG; D011983:Receptors, Purinergic; D010566:Virulence Factors, Bordetella; D013481:Superoxides; D010660:Phenylisopropyladenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); C048599:N(6)-cyclopentyladenosine; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D037342:Pertussis Toxin; D000241:Adenosine