1.Rutgers New Jersey Medical School, 185 South Orange Ave., University Heights, Newark, NJ 07103, USA.
J Leukoc Biol. 2013 Dec;94(6):1309-15. doi: 10.1189/jlb.0113043. Epub 2013 Aug 6.
The alternatively activated macrophage phenotype induced by IL-10 is called M2c. Adenosine is an endogenous purine nucleoside that accumulates in the extracellular space in response to metabolic disturbances, hypoxia, inflammation, physical damage, or apoptosis. As adenosine is known to regulate classically activated M1 and IL4- and IL-13-activated M2a macrophages, the goal of the present study was to explore its effects on M2c macrophages. We found that adenosine augmented the IL-10-induced expression of TIMP-1 and arginase-1 by the mouse macrophage cell line RAW 264.7 and by mouse BMDMs. The effects of AR stimulation on IL-10-induced TIMP-1 or arginase-1 expression were lacking in A2BAR KO macrophages. The role of A2BAR on TIMP-1 production of RAW 264.7 cells was confirmed with specific agonist BAY606583 and antagonist PSB0788. AR stimulation augmented IL-10-induced STAT3 phosphorylation in macrophages, and pharmacological inhibition or silencing of STAT3 using siRNA reduced the stimulatory effect of AR stimulation on TIMP-1 production. In contrast to its stimulatory effect on IL-10-induced STAT3 activation, adenosine inhibited IL-6-induced STAT3 phosphorylation and SAA3 expression. In conclusion, adenosine enhances IL-10-induced STAT3 signaling and M2c macrophage activation.
IL-10 诱导的交替激活的巨噬细胞表型被称为 M2c。腺苷是一种内源性嘌呤核苷，在代谢紊乱、缺氧、炎症、物理损伤或细胞凋亡时会在细胞外间隙积累。由于腺苷已知可调节经典激活的 M1 和 IL4 和 IL-13 激活的 M2a 巨噬细胞，本研究的目的是探讨其对 M2c 巨噬细胞的影响。我们发现，腺苷增强了鼠巨噬细胞系 RAW 264.7 和鼠 BMDMs 中 IL-10 诱导的 TIMP-1 和精氨酸酶-1的表达。在 A2BAR KO 巨噬细胞中，AR 刺激对 IL-10 诱导的 TIMP-1 或精氨酸酶-1 表达的影响缺失。用特异性激动剂 BAY606583 和拮抗剂 PSB0788 证实了 A2BAR 在 RAW 264.7 细胞 TIMP-1 产生中的作用。AR 刺激增强了巨噬细胞中 IL-10 诱导的 STAT3 磷酸化，而使用 siRNA 抑制或沉默 STAT3 则降低了 AR 刺激对 TIMP-1 产生的刺激作用。与腺苷对 IL-10 诱导的 STAT3 激活的刺激作用相反，腺苷抑制了 IL-6 诱导的 STAT3 磷酸化和 SAA3 表达。总之，腺苷增强了 IL-10 诱导的 STAT3 信号通路和 M2c 巨噬细胞的激活。
