Adenosine augments IL-10 production by macrophages through an A 2B receptor-mediated posttranscriptional mechanism

Zoltán H. Németh, Carol S. Lutz, Balázs Csóka, Edwin A. Deitch, S. Joseph Leibovich, William C. Gause, Masahide Tone, Pál Pacher, E. Sylvester Vizi, György Haskó

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Adenosine receptor ligands have anti-inflammatory effects and modulate immune responses by up-regulating IL-10 production by immunostimulated macrophages. The adenosine receptor family comprises G protein-coupled heptahelical transmembrane receptors classified into four types: A1, A2A, A2B, and A3. Our understanding of the signaling mechanisms leading to enhanced IL-10 production following adenosine receptor occupancy on macrophages is limited. In this study, we demonstrate that adenosine receptor occupancy increases IL-10 production by LPS-stimulated macrophages without affecting IL-10 promoter activity and IL-10 mRNA levels, indicating a posttranscriptional mechanism. Transfection experiments with reporter constructs containing sequences corresponding to the AU-rich 3′-untranslated region (UTR) of IL-10 mRNA confirmed that adenosine receptor activation acts by relieving the translational repressive effect of the IL-10 3′-UTR. By contrast, adenosine receptor activation failed to liberate the translational arrest conferred by the 3′-UTR of TNF-α mRNA. The IL-10 3′-UTR formed specific complexes with proteins present in cytoplasmic extracts of RAW 264.7 cells. Adenosine enhanced binding of proteins to a region of the IL-10 3′-UTR containing the GUAUUUAUU nonamer. The stimulatory effect of adenosine on IL-10 production was mediated through the A2B receptor, because the order of potency of selective agonists was 5′-N-ethylcarboxamidoadenosine (NECA) > N6-(3-iodobenzyl)- adenosine-5′-N-methyluronamide (IB-MECA) > 2-chloro-N 6-cyclopentyladenosine (CCPA) = 2-p-(2-carboxyethyl)phenethylamino- 5′-N-ethyl-carboxamidoadenosine (CGS-21680). Also, the selective A 2B antagonist, alloxazine, prevented the effect of adenosine. Collectively, these studies identify a novel pathway in which activation of a G protein-coupled receptor augments translation of an anti-inflammatory gene.

Original languageEnglish
Pages (from-to)8260-8270
Number of pages11
JournalJournal of Immunology
Issue number12
Publication statusPublished - Dec 15 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Németh, Z. H., Lutz, C. S., Csóka, B., Deitch, E. A., Leibovich, S. J., Gause, W. C., Tone, M., Pacher, P., Vizi, E. S., & Haskó, G. (2005). Adenosine augments IL-10 production by macrophages through an A 2B receptor-mediated posttranscriptional mechanism. Journal of Immunology, 175(12), 8260-8270.