title: Adenosine augments IL-10 production by microglial cells through an A2B adenosine receptor-mediated process.
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(1)AR, A(2A)AR, A(2B)AR, and A(3)AR. 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(2B)AR antagonist MRS1754 prevented the effect of NECA, we conclude that the stimulatory effect of adenosine on IL-10 production is mediated by the A(2B)AR. 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 A(2B)ARs augment IL-10 production by activated murine microglia.
authors: Department of Surgery, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
authors: Balázs
authors: B
authors: Koscsó
authors: Balázs
authors: B
authors: Csóka
authors: Zsolt
authors: Z
authors: Selmeczy
authors: Leonóra
authors: L
authors: Himer
authors: Pál
authors: P
authors: Pacher
authors: László
authors: L
authors: Virág
authors: György
authors: G
authors: Haskó
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000241:Adenosine / Q000276:immunology* / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000276:immunology / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000276:immunology / Q000494:pharmacology; D000818:Animals; D050882:CREB-Binding Protein / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000276:immunology; D011687:Purines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology; D043704:Receptor, Adenosine A2B / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D000081:Acetamides; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000700:Analgesics; C556062:IL10 protein, mouse; C423842:N-(4-cyanophenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy)acetamide; D009419:Nerve Tissue Proteins; D011687:Purines; D012333:RNA, Messenger; D043704:Receptor, Adenosine A2B; D016753:Interleukin-10; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D000241:Adenosine