Adenosine promotes alternative macrophage activation via A2A and A2B receptors

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. We show 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 (EC50=261.8 nM) and TIMP‐1 production (EC50=80.67 nM), and both pharmacologic and genetic blockade of A2B receptors prevented the effect of NECA. A2A receptors also contributed to the adenosine augmentation of IL4‐induced TIMP‐1 release, as both adenosine and NECA were less efficacious in augmenting TIMP‐1 release by A2A 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. Csóka, B., Selmeczy, Z., Koscsó, B., Németh, Z. H., Pacher, P., Murray, P. J., Kepka‐Lenhart, D., Morris S. M., Jr., Gause, W. C., Leibovich, S. J., Haskó, G. Adenosine promotes alternative macrophage activation via A2A and A2B receptors. FASEB J. 26, 376–386 (2012). www.fasebj.org