Document Detail


Adenosine augments IL-10 production by microglial cells through an A2B adenosine receptor-mediated process.
MedLine Citation:
PMID:  22116830     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Balázs Koscsó; Balázs Csóka; Zsolt Selmeczy; Leonóra Himer; Pál Pacher; László Virág; György Haskó
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-11-23
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  188     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2011-12-21     Completed Date:  2012-02-16     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  445-53     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Acetamides / pharmacology
Adenosine / immunology*,  pharmacology
Adenosine A2 Receptor Agonists / immunology,  pharmacology
Adenosine A2 Receptor Antagonists / pharmacology
Analgesics / immunology,  pharmacology
Animals
CREB-Binding Protein / immunology,  metabolism
Cell Line
Interleukin-10 / biosynthesis,  immunology*
MAP Kinase Signaling System / drug effects,  immunology*
Mice
Microglia / cytology,  immunology*,  metabolism
Nerve Tissue Proteins / agonists,  antagonists & inhibitors,  immunology*,  metabolism
Phosphorylation / drug effects,  immunology
Promoter Regions, Genetic / immunology
Purines / pharmacology
RNA, Messenger / biosynthesis,  immunology
Receptor, Adenosine A2B / immunology*,  metabolism
Transcription, Genetic / drug effects,  immunology
p38 Mitogen-Activated Protein Kinases / immunology,  metabolism
Grant Support
ID/Acronym/Agency:
R01 GM066189/GM/NIGMS NIH HHS; R01 GM066189-08/GM/NIGMS NIH HHS; R01GM66189/GM/NIGMS NIH HHS; R56 GM066189/GM/NIGMS NIH HHS; Z99 AA999999/AA/NIAAA NIH HHS; ZIA AA000375-06/AA/NIAAA NIH HHS
Chemical
Reg. No./Substance:
0/Acetamides; 0/Adenosine A2 Receptor Agonists; 0/Adenosine A2 Receptor Antagonists; 0/Analgesics; 0/Crebbp protein, mouse; 0/IL10 protein, mouse; 0/N-(4-cyanophenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy)acetamide; 0/Nerve Tissue Proteins; 0/Purines; 0/RNA, Messenger; 0/Receptor, Adenosine A2B; 130068-27-8/Interleukin-10; EC 2.3.1.48/CREB-Binding Protein; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; K72T3FS567/Adenosine
Comments/Corrections

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