Adenosine augments IL-10 production by microglial cells through an A 2B adenosine receptor-mediated process

Balázs Koscsó, Balázs Csóka, Zsolt Selmeczy, Leonóra Himer, Pál Pacher, L. Virag, G. Haskó

Research output: Contribution to journalArticle

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Abstract

Microglia are activated by pathogen-associated molecular patterns and produce proinflammatory cytokines, such as TNF-α, IL-6, and IL-12, and the anti-inflammatory cytokine IL-10. Adenosine is an endogenous purine nucleoside and a ligand of four G protein-coupled adenosine receptors (ARs), which are the A 1AR, A 2AAR, A 2BAR, and A 3AR. ARs have been shown to suppress TNF-α production by microglia, but their role in regulating IL-10 production has not been studied. In this study, we demonstrate that adenosine augments IL-10 production by activated murine microglia while suppressing the production of proinflammatory cytokines. Because the order of potency of selective AR agonists in inducing IL-10 production was NECA > IB-MECA > CCPA ≥CGS21680, and the A 2BAR antagonist MRS1754 prevented the effect of NECA, we conclude that the stimulatory effect of adenosine on IL-10 production is mediated by the A 2BAR. Mechanistically, adenosine augmented IL-10 mRNA accumulation by a transcriptional process. Using mutant IL-10 promoter constructs we showed that a CREB-binding region in the promoter mediated the augmenting effect of adenosine on IL-10 transcription. Chromatin immunoprecipitation analysis demonstrated that adenosine induced CREB phosphorylation at the IL-10 promoter. Silencing CREB using lentivirally delivered short hairpin RNA blocked the enhancing effect of adenosine on IL-10 production, confirming a role for CREB in mediating the stimulatory effect of adenosine on IL-10 production. In addition, adenosine augmented IL-10 production by stimulating p38 MAPK. Collectively, our results establish that A2BARs augment IL-10 production by activated murine microglia.

Original languageEnglish
Pages (from-to)445-453
Number of pages9
JournalJournal of Immunology
Volume188
Issue number1
DOIs
Publication statusPublished - Jan 1 2012

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Adenosine A2B Receptors
Interleukin-10
Adenosine
Microglia
Adenosine-5'-(N-ethylcarboxamide)
Purinergic P1 Receptors
Cytokines
Purinergic P1 Receptor Agonists
Purine Nucleosides
Chromatin Immunoprecipitation
p38 Mitogen-Activated Protein Kinases
Interleukin-12

ASJC Scopus subject areas

  • Immunology

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Adenosine augments IL-10 production by microglial cells through an A 2B adenosine receptor-mediated process. / Koscsó, Balázs; Csóka, Balázs; Selmeczy, Zsolt; Himer, Leonóra; Pacher, Pál; Virag, L.; Haskó, G.

In: Journal of Immunology, Vol. 188, No. 1, 01.01.2012, p. 445-453.

Research output: Contribution to journalArticle

Koscsó, Balázs ; Csóka, Balázs ; Selmeczy, Zsolt ; Himer, Leonóra ; Pacher, Pál ; Virag, L. ; Haskó, G. / Adenosine augments IL-10 production by microglial cells through an A 2B adenosine receptor-mediated process. In: Journal of Immunology. 2012 ; Vol. 188, No. 1. pp. 445-453.
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AU - Koscsó, Balázs

AU - Csóka, Balázs

AU - Selmeczy, Zsolt

AU - Himer, Leonóra

AU - Pacher, Pál

AU - Virag, L.

AU - Haskó, G.

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AB - Microglia are activated by pathogen-associated molecular patterns and produce proinflammatory cytokines, such as TNF-α, IL-6, and IL-12, and the anti-inflammatory cytokine IL-10. Adenosine is an endogenous purine nucleoside and a ligand of four G protein-coupled adenosine receptors (ARs), which are the A 1AR, A 2AAR, A 2BAR, and A 3AR. ARs have been shown to suppress TNF-α production by microglia, but their role in regulating IL-10 production has not been studied. In this study, we demonstrate that adenosine augments IL-10 production by activated murine microglia while suppressing the production of proinflammatory cytokines. Because the order of potency of selective AR agonists in inducing IL-10 production was NECA > IB-MECA > CCPA ≥CGS21680, and the A 2BAR antagonist MRS1754 prevented the effect of NECA, we conclude that the stimulatory effect of adenosine on IL-10 production is mediated by the A 2BAR. Mechanistically, adenosine augmented IL-10 mRNA accumulation by a transcriptional process. Using mutant IL-10 promoter constructs we showed that a CREB-binding region in the promoter mediated the augmenting effect of adenosine on IL-10 transcription. Chromatin immunoprecipitation analysis demonstrated that adenosine induced CREB phosphorylation at the IL-10 promoter. Silencing CREB using lentivirally delivered short hairpin RNA blocked the enhancing effect of adenosine on IL-10 production, confirming a role for CREB in mediating the stimulatory effect of adenosine on IL-10 production. In addition, adenosine augmented IL-10 production by stimulating p38 MAPK. Collectively, our results establish that A2BARs augment IL-10 production by activated murine microglia.

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