Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes

Amrey A. Link, Tomoshige Kino, James A. Worth, Jennifer L. McGuire, Marianna L. Crane, George P. Chrousos, Ronald L. Wilder, Ilia J. Elenkov

Research output: Contribution to journalArticle

199 Citations (Scopus)

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- carbonylethyl)phenylethylamino-5'-N-ethylcarboxamidoadenosine (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-β-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.

Original languageEnglish
Pages (from-to)436-442
Number of pages7
JournalJournal of Immunology
Volume164
Issue number1
Publication statusPublished - 1 Jan 2000
Externally publishedYes

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Purinergic P1 Receptors
Interleukin-12
Adenosine-5'-(N-ethylcarboxamide)
Monocytes
Interleukin-10
Ligands
Adenosine
Cyclic AMP-Dependent Protein Kinases
4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone
Phosphodiesterase Inhibitors
Protein Kinase Inhibitors
Immunosuppressive Agents
Cellular Immunity
2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
Anti-Inflammatory Agents
Cytokines
Wounds and Injuries
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Immunology

Cite this

Link, A. A., Kino, T., Worth, J. A., McGuire, J. L., Crane, M. L., Chrousos, G. P., ... Elenkov, I. J. (2000). Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. Journal of Immunology, 164(1), 436-442.

Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. / Link, Amrey A.; Kino, Tomoshige; Worth, James A.; McGuire, Jennifer L.; Crane, Marianna L.; Chrousos, George P.; Wilder, Ronald L.; Elenkov, Ilia J.

In: Journal of Immunology, Vol. 164, No. 1, 01.01.2000, p. 436-442.

Research output: Contribution to journalArticle

Link, AA, Kino, T, Worth, JA, McGuire, JL, Crane, ML, Chrousos, GP, Wilder, RL & Elenkov, IJ 2000, 'Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes', Journal of Immunology, vol. 164, no. 1, pp. 436-442.
Link AA, Kino T, Worth JA, McGuire JL, Crane ML, Chrousos GP et al. Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. Journal of Immunology. 2000 Jan 1;164(1):436-442.
Link, Amrey A. ; Kino, Tomoshige ; Worth, James A. ; McGuire, Jennifer L. ; Crane, Marianna L. ; Chrousos, George P. ; Wilder, Ronald L. ; Elenkov, Ilia J. / Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. In: Journal of Immunology. 2000 ; Vol. 164, No. 1. pp. 436-442.
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AU - Kino, Tomoshige

AU - Worth, James A.

AU - McGuire, Jennifer L.

AU - Crane, Marianna L.

AU - Chrousos, George P.

AU - Wilder, Ronald L.

AU - Elenkov, Ilia J.

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N2 - 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- carbonylethyl)phenylethylamino-5'-N-ethylcarboxamidoadenosine (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-β-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.

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