Activation of the A(3) adenosine receptor inhibits fMLP-induced Rac activation in mouse bone marrow neutrophils.
Activation of the A(3) adenosine receptor inhibits fMLP-induced Rac activation in mouse bone marrow neutrophils.
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DOI：
10.1016/j.bcp.2010.02.002
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发表时间：
2010-06-01
影响因子：
5.8
通讯作者：
Auchampach, John A.
中科院分区：
文献类型：
--
作者：
van der Hoeven, Dharini;Gizewski, Elizabeth T.;Auchampach, John A.
腺苷从受损或缺氧组织中释放出来，在这些组织中它发挥多种抗炎作用，包括抑制中性粒细胞的功能。尽管先前的大多数研究都涉及A2AAR，但我们最近发现，大量表达的A3AR的选择性激活可抑制中性粒细胞超氧化物的产生和趋化性，这为A3AR激动剂在炎症实验动物模型中的功效提供了一种潜在的机制解释。在本研究中，我们假设A3AR通过抑制单体GTP酶Rac来抑制中性粒细胞的功能，Rac是趋化因子引导的中性粒细胞迁移和超氧化物产生的核心调节因子。我们发现，使用一种基于ELISA的检测所有三种Rac异构体的方法，用高选择性A3AR激动剂CP - 532,903预处理中性粒细胞可降低fMLP诱导的Rac激活。CP - 532,903还抑制fMLP诱导的F - 肌动蛋白形成，这是与中性粒细胞迁移相关的Rac下游效应功能，但不抑制ERK1/2或p38的激活。用CP - 532,903预处理中性粒细胞不会刺激cAMP的产生，也不会改变fMLP诱导的钙瞬变，这表明A3AR刺激不是通过抑制Ca2 +信号传导、提高细胞内cAMP浓度或通过交叉脱敏fMLP受体来抑制Rac激活或中性粒细胞活性。我们的研究结果表明，A3AR的激活通过干扰单体GTP酶Rac来传递信号抑制中性粒细胞功能，从而有助于腺苷的抗炎作用。
Adenosine is released from injured or hypoxic tissues where it exerts numerous anti-inflammatory effects including suppression of neutrophil functions. Although most previous work has implicated the A2AAR, we have recently shown that selective activation of the abundantly expressed A3AR inhibits neutrophil superoxide production and chemotaxis providing a potential mechanistic explanation for the efficacy of A3AR agonists in experimental animal models of inflammation. In this study, we hypothesized that the A3AR suppresses neutrophil functions by inhibiting the monomeric GTPase Rac, a central regulator of chemokine-directed neutrophil migration and superoxide production. We found that pre-treating neutrophils with the highly selective A3AR agonist CP-532,903 reduced fMLP-induced Rac activation using an ELISA-based assay that detects all three Rac isoforms. CP-532,903 also inhibited fMLP-induced F-actin formation, a downstream effector function of Rac relevant to neutrophil migration, but not activation of ERK1/2 or p38. Pre-treating neutrophils with CP-532,903 did not stimulate cAMP production or alter fMLP-induced calcium transients, implicating that A3AR stimulation does not inhibit Rac activation or neutrophil activities by suppressing Ca2+ signaling, elevating the intracellular concentration of cAMP, or by cross-desensitizing fMLP receptors. Our results suggest that activation of the A3AR signals to suppress neutrophil functions by interfering with the monomeric GTPase Rac, thus contributing to the ant-inflammatory actions of adenosine.
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56.9
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