Adenosine promotes alternative macrophage activation via A 2Aand A 2B receptors

Balázs Csóka, Zsolt Selmeczy, Balázs Koscsó, Zoltán H. Németh, Pál Pacher, Peter J. Murray, Diane Kepka-Lenhart, Sidney M. Morris, William C. Gause, S. Joseph Leibovich, György Haskó

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167 Citations (Scopus)


Adenosine has been implicated in suppressing the proinflammatory responses of classically activated macrophages induced by Th1 cytokines. Alternative macrophage activation is induced by the Th2 cytokines interleukin (IL)-4 and IL-13; however, the role of adenosine in governing alternative macrophage activation is unknown.Weshow here that adenosine treatment of IL-4- or IL-13-activated macrophages augments the expression of alternative macrophage markers arginase-1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), and macrophage galactose-type C-type lectin-1. The stimulatory effect of adenosine required primarily A2B receptors because the nonselective adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) increased both arginase activity (EC 50=261.8 nM) and TIMP-1 production (EC 50=80.67 nM), and both pharmacologic and genetic blockade of A 2B receptors prevented the effect of NECA. A 2A receptors also contributed to the adenosine augmentation of IL-4-induced TIMP-1 release, as both adenosine and NECA were less efficacious in augmenting TIMP-1 release by A 2A receptor-deficient than control macrophages. Of the transcription factors known to drive alternative macrophage activation, CCAAT-enhancer-binding protein β was required, while cAMP response element-binding protein and signal transducer and activator of transcription 6 were dispensable in mediating the effect of adenosine. We propose that adenosine receptor activation suppresses inflammation and promotes tissue restitution, in part, by promoting alternative macrophage activation.

Original languageEnglish
Pages (from-to)376-386
Number of pages11
JournalFASEB Journal
Issue number1
Publication statusPublished - Jan 1 2012


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ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Csóka, B., Selmeczy, Z., Koscsó, B., Németh, Z. H., Pacher, P., Murray, P. J., Kepka-Lenhart, D., Morris, S. M., Gause, W. C., Leibovich, S. J., & Haskó, G. (2012). Adenosine promotes alternative macrophage activation via A 2Aand A 2B receptors. FASEB Journal, 26(1), 376-386.