1. Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes.
- Author
-
Link AA, Kino T, Worth JA, McGuire JL, Crane ML, Chrousos GP, Wilder RL, and Elenkov IJ
- Subjects
- Adenosine analogs & derivatives, Adenosine antagonists & inhibitors, Adenosine pharmacology, Adenosine physiology, Adenosine-5'-(N-ethylcarboxamide) pharmacology, Caffeine analogs & derivatives, Caffeine pharmacology, Cyclic AMP physiology, Cyclic AMP-Dependent Protein Kinases physiology, Dose-Response Relationship, Immunologic, Female, Humans, Interleukin-10 biosynthesis, Interleukin-10 blood, Interleukin-10 metabolism, Interleukin-12 blood, Ligands, Lipopolysaccharides antagonists & inhibitors, Lipopolysaccharides pharmacology, Male, Monocytes drug effects, Monocytes immunology, Phenethylamines antagonists & inhibitors, Phenethylamines pharmacology, Purinergic P1 Receptor Agonists, Purinergic P1 Receptor Antagonists, Receptor, Adenosine A2A, Receptor, Adenosine A3, Receptors, Purinergic P1 physiology, Signal Transduction drug effects, Adenosine metabolism, Immunosuppressive Agents pharmacology, Interleukin-12 antagonists & inhibitors, Interleukin-12 biosynthesis, Monocytes metabolism, Receptors, Purinergic P1 metabolism
- 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.
- Published
- 2000
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