Uridine 5′-Diphosphate Induces Chemokine Expression in Microglia and Astrocytes through Activation of the P2Y6 Receptor
Uridine 5′-Diphosphate Induces Chemokine Expression in Microglia and Astrocytes through Activation of the P2Y6 Receptor
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DOI：
10.4049/jimmunol.1000212
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发表时间：
2011-03-15
影响因子：
4.4
通讯作者：
Joe, Eun-hye
中科院分区：
文献类型：
--
作者：
Kim, Beomsue;Jeong, Hey-kyeong;Joe, Eun-hye
趋化因子通过将炎性细胞募集到损伤部位而在炎症中起关键作用。在这项研究中，我们发现UDP通过激活P2 Y诱导小胶质细胞、星形胶质细胞和切片培养物中趋化因子CCL 2（MCP-1）和CCL 3（MIP-1 α）的表达（6）。有趣的是，CCL 2比CCL 3更高表达。然而，响应于UDP的CCL 2合成动力学在小胶质细胞和星形胶质细胞中不同;小胶质细胞快速产生少量的CCL 2，而星形胶质细胞持续合成大量的CCL 2，导致高的趋化因子的最终水平。在存在P2 Y（6）的特异性拮抗剂（MRS 2578）或针对P2 Y（6）基因的小干扰RNA的情况下，UDP诱导的趋化因子表达降低。抑制磷脂酶C和钙增加，Gq偶联P2 Y的下游信号传导途径（6），降低UDP诱导的趋化因子表达。UDP激活了两个钙激活的转录因子，NFATc 1和c2。此外，钙调磷酸酶（磷酸酶激活NFAT）和NFAT的抑制剂减少UDP诱导的趋化因子的合成。我们还发现，使用transmigration分析，UDP处理的星形胶质细胞招募单核细胞。这些结果表明，UDP通过激活P2 Y（6）受体诱导损伤脑的小胶质细胞和星形胶质细胞中的趋化因子表达。免疫学杂志，2011，186：3701-3709。
Chemokines play critical roles in inflammation by recruiting inflammatory cells to injury sites. In this study, we found that UDP induced expression of chemokines CCL2 (MCP-1) and CCL3 (MIP-1 alpha) in microglia, astrocytes, and slice cultures by activation of P2Y(6). Interestingly, CCL2 was more highly expressed than CCL3. However, CCL2 synthesis kinetics in response to UDP differed in microglia and astrocytes; microglia rapidly produced small amounts of CCL2, whereas astrocytes continuously synthesized large amounts of CCL2, resulting in a high ultimate level of the chemokine. UDP-induced chemokine expression was reduced in the presence of a specific antagonist of P2Y(6) (MRS2578) or small interfering RNA directed against the P2Y(6) gene. Inhibition of phospholipase C and calcium increase, downstream signaling pathways of Gq-coupled P2Y(6), reduced UDP-induced chemokine expression. UDP activated two calcium-activated transcription factors, NFATc1 and c2. Furthermore, inhibitors of calcineurin (a phosphatase activating NFAT) and NFAT reduced UDP-induced chemokine synthesis. We also found, using a transmigration assay, that UDP-treated astrocytes recruited monocytes. These results suggest that UDP induces chemokine expression in microglia and astrocytes of the injured brain by activation of P2Y(6) receptors. The Journal of Immunology, 2011, 186: 3701-3709.