title: Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes.
abstract: Adenosine (ADO) exerts potent anti-inflammatory and immunosuppressive effects. In this paper we address the possibility that these effects are partly mediated by inhibition of the secretion of IL-12, a proinflammatory cytokine and a major inducer of Th1 responses. We demonstrate that 5'-N-ethylcarboxamidoadenosine (NECA), a nonspecific ADO analogue, and 2-p-(2-carbonyl-ethyl)phenylethylamino-5'-N-ethylcarboxamidoadenos ine (CGS-21680), a specific A2a receptor agonist, dose-dependently inhibited, in whole blood ex vivo and monocyte cultures, the production of human IL-12 induced by LPS and Stapholococcus aureus Cowan strain 1. However, the A1 receptor agonist 2-Chloro-N6-cyclopentyladenosine and the A3 receptor agonists N6-Benzyl-NECA and 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-be ta-d -ribofuranuronamide expressed only weak inhibitory effects. On the other hand, NECA 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 implies that these effects are mediated by A2a receptor signaling rather than by intracellular toxicity of ADO analogue's metabolites. Moreover, CGS-21680 inhibited IL-12 production independently of endogenous IL-10 induction, because anti-IL-10 Abs failed to prevent its effect. The selective A2a antagonist 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 stimulates IL-10 production by human monocytes. Through this mechanism, ADO released in excess during inflammatory and ischemic conditions, or tissue injury, may contribute to selective suppression of Th1 responses and cellular immunity.
authors.affiliation: Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Link
authors.forename: T
authors.initials: T
authors.lastname: Kino
authors.forename: J A
authors.initials: JA
authors.lastname: Worth
authors.forename: J L
authors.initials: JL
authors.lastname: McGuire
authors.forename: M L
authors.initials: ML
authors.lastname: Crane
authors.forename: G P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: R L
authors.initials: RL
authors.lastname: Wilder
authors.forename: I J
authors.initials: IJ
authors.lastname: Elenkov
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D002110:Caffeine / Q000031:analogs & derivatives / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000097:blood; D008024:Ligands; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010627:Phenethylamines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007166:Immunosuppressive Agents; D008024:Ligands; D008070:Lipopolysaccharides; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D016753:Interleukin-10; C081320:8-(3-chlorostyryl)caffeine; D018664:Interleukin-12; D019830:Adenosine-5'-(N-ethylcarboxamide); D002110:Caffeine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine