P2X7-like receptor activation in astrocytes increases chemokine monocyte chemoattractant protein-1 expression via mitogen-activated protein kinase
P2X7-like receptor activation in astrocytes increases chemokine monocyte chemoattractant protein-1 expression via mitogen-activated protein kinase
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DOI：
10.1523/jneurosci.21-18-07135.2001
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发表时间：
2001-09-15
影响因子：
5.3
通讯作者：
MacVicar, BA
中科院分区：
文献类型：
--
作者：
Panenka, W;Jijon, H;MacVicar, BA
创伤或炎症后CNS中的白细胞浸润部分由星形胶质细胞中的趋化因子单核细胞趋化蛋白-1（MCP-1）的上调触发。然而，诱导星形胶质细胞中MCP-1上调的信号是未知的。我们已经研究了ATP P2X7受体激活的作用，因为ATP是在创伤和炎症中释放的细胞间信号传导物质，P2X7受体参与免疫系统信号传导。星形胶质细胞在原代细胞培养和急性分离的海马P2X7受体免疫阳性。在星形胶质细胞培养物中，应用选择性P2X7激动剂，苯甲酰-苯甲酰ATP（Bz-ATP），激活MAP激酶细胞外信号受体激活激酶1（ERK 1），ERK 2和p38。嘌呤能拮抗剂抑制这种激活与提示P2X7受体的配置文件。Bz-ATP还增加了培养的星形胶质细胞中MCP-1的表达，并且P2X7拮抗剂再次阻止了这种增加。阻断ERK 1/ERK 2或p38通路（分别用PD98059或SB 203580）可显著抑制Bz-ATP诱导的MCP-1表达。两种拮抗剂的共同应用引起了更大的抑郁症。我们还测试了ATP受体激活在皮质切除术（一种体内创伤模型）中诱导MCP-1上调的作用。这种皮质创伤模型先前显示主要在星形胶质细胞中增加体内MCP-1表达。苏拉明，广谱嘌呤受体拮抗剂，显着抑制快速（3小时）创伤诱导的MCP-1 mRNA的增加。这些数据表明，在星形胶质细胞中的嘌呤能递质受体在调节趋化因子的合成是重要的。ATP对星形胶质细胞中MCP-1的调节可能在介导与造血炎性细胞的通讯中起重要作用。
Leukocyte infiltration in the CNS after trauma or inflammation is triggered in part by upregulation of the chemokine, monocyte chemoattractant protein-1 (MCP-1), in astrocytes. However the signals that induce the upregulation of MCP-1 in astrocytes are unknown. We have investigated the roles for ATP P2X7 receptor activation because ATP is an intercellular signaling transmitter that is released in both trauma and inflammation and P2X7 receptors are involved in immune system signaling. Astrocytes in primary cell culture and acutely isolated from the hippocampus were immunopositive for P2X7 receptors. In astrocyte cultures, application of the selective P2X7 agonist, benzoyl-benzoyl ATP (Bz-ATP), activated MAP kinases extracellular signal receptor-activated kinase 1 (ERK1), ERK2, and p38. Purinergic antagonists depressed this activation with a profile suggesting P2X7 receptors. Bz-ATP also increased MCP-1 expression in cultured astrocytes, and again P2X7 antagonists prevented this increase. Blocking either the ERK1/ERK2 or the p38 pathway (with PD98059 or SB203580, respectively) significantly inhibited Bz-ATP-induced MCP-1 expression. Coapplication of both antagonists caused a greater depression. We also tested the roles for ATP receptor activation in inducing MCP-1 upregulation in corticectomy, an in vivo model of trauma. This model of cortical trauma was previously shown to increase MCP-1 expression in vivo principally in astrocytes. Suramin, a wide-spectrum purinergic receptor antagonist, significantly depressed the rapid (3 hr) trauma-induced increase in MCP-1 mRNA. These data indicate that purinergic transmitter receptors in astrocytes are important in regulating chemokine synthesis. The regulation of MCP-1 in astrocytes by ATP may be important in mediating communication with hematopoietic inflammatory cells.