Activation of the A3 adenosine receptor suppresses superoxide production and chemotaxis of mouse bone marrow neutrophils
Activation of the A3 adenosine receptor suppresses superoxide production and chemotaxis of mouse bone marrow neutrophils
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DOI：
10.1124/mol.108.048066
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发表时间：
2008-09-01
影响因子：
3.6
通讯作者：
Auchampach, John A.
中科院分区：
文献类型：
--
作者：
van der Hoeven, Dharini;Wan, Tina C.;Auchampach, John A.
腺苷在损伤/缺血组织中形成，在那里它抑制免疫系统几乎所有细胞的活动。腺苷的大多数抗炎作用归因于通过G(s)蛋白偶联的A(2A)腺苷受体（AR）的信号传导。在此，我们报道A(3)AR在从骨髓分离的小鼠中性粒细胞中高度表达。用(2S, 3S, 4R, 5R)-3 - 氨基 - 5 - [6 - (2,5 - 二氯苄基氨基)嘌呤 - 9 - 基] - 4 - 羟基四氢呋喃 - 2 - 羧酸甲酰胺（CP - 532,903）选择性激活A(3)AR，可有效抑制由各种激活剂诱导的小鼠骨髓中性粒细胞超氧化物产生和趋化性。在使用从A(2A)AR和A(3)AR基因“敲除”小鼠获得的中性粒细胞的实验中，证实了CP - 532,903的选择性。在硫代乙醇酸盐诱导的炎症模型中，用CP - 532,903治疗小鼠通过特异性激活A(3)AR抑制白细胞向腹腔的募集。总之，我们的研究结果支持A(3)AR有助于腺苷对中性粒细胞的抗炎作用这一理论，并为A(3)AR激动剂在炎症动物模型中的功效（即抑制中性粒细胞介导的组织损伤）提供了一种潜在的机制解释。
Adenosine is formed in injured/ischemic tissues, where it suppresses the actions of essentially all cells of the immune system. Most of the anti-inflammatory actions of adenosine have been attributed to signaling through the G(s) protein-coupled A(2A) adenosine receptor (AR). Here, we report that the A(3)AR is highly expressed in murine neutrophils isolated from bone marrow. Selective activation of the A(3)AR with (2S, 3S, 4R, 5R)-3-amino5-[6-(2,5-dichlorobenzylamino) purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-532,903) potently inhibited mouse bone marrow neutrophil superoxide generation and chemotaxis induced by various activating agents. The selectivity of CP-532,903 was confirmed in assays using neutrophils obtained from A(2A)AR and A(3)AR gene "knockout" mice. In a model of thioglycollate-induced inflammation, treating mice with CP-532,903 inhibited recruitment of leukocytes into the peritoneum by specifically activating the A(3)AR. Collectively, our findings support the theory that the A(3)AR contributes to the anti-inflammatory actions of adenosine on neutrophils and provide a potential mechanistic explanation for the efficacy of A(3)AR agonists in animal models of inflammation (i.e., inhibition of neutrophil-mediated tissue injury).