title: Adenosine promotes alternative macrophage activation via A2A and A2B receptors.
abstract: 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 A(2B) 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.
authors.affiliation: Department of Surgery, UMDNJ-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Balázs
authors.initials: B
authors.lastname: Csóka
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Selmeczy
authors.forename: Balázs
authors.initials: B
authors.lastname: Koscsó
authors.forename: Zoltán H
authors.initials: ZH
authors.lastname: Németh
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
authors.forename: Diane
authors.initials: D
authors.lastname: Kepka-Lenhart
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Morris
authors.forename: William C
authors.initials: WC
authors.lastname: Gause
authors.forename: S Joseph
authors.initials: SJ
authors.lastname: Leibovich
authors.forename: György
authors.initials: G
authors.lastname: Haskó
mesh_terms: D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D018793:Interleukin-13; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014665:Vasodilator Agents; D015847:Interleukin-4; D019830:Adenosine-5'-(N-ethylcarboxamide); C544448:Arg1 protein, mouse; D001119:Arginase; D000241:Adenosine