Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
J Neurochem. 2010 May;113(3):772-83. doi: 10.1111/j.1471-4159.2010.06646.x. Epub 2010 Feb 17.
Neurodegenerative and neuroinflammatory disorders are commonly associated with local chemokine release. In other way, emerging data indicate that the prostaglandin E2 (PGE(2)), one of the major prostaglandins produced in the brain, play a central role in several pathological diseases. In this study, we investigated the relationship between CXCL12, cyclooxygenase (COX)-2 and PGE(2) in human brain cells. CXCL12 induced COX-2 and secretion of PGE(2) in a dose-dependent manner in human astrocytes. This induction was abolished by treatment with pertussis toxin and AMD3100, confirming the role of CXCR4 signaling. The nuclear factor-kappaB involvement was confirmed by using pyrrolidine dithiocarbamate, and with transient transfection assays. Over-expression of inhibitory proteins of nuclear factor-kappaB abrogated COX-2 induction, and CXCL12 induced p65/relA translocation. Culture supernatants from CXCL12-treated astrocytes reduced viability of neuroblastoma cells, and COX inhibitors abrogated this toxicity. Therefore, the relationship between chemokines and PGs could differentially influence the pathogenic network responsible for neurodegeneration.
神经退行性和神经炎性疾病通常与局部趋化因子释放有关。另一方面，新出现的数据表明，前列腺素 E2 (PGE2)，大脑中产生的主要前列腺素之一，在几种病理疾病中起着核心作用。在这项研究中，我们研究了人脑细胞中 CXCL12、环氧化酶 (COX)-2 和 PGE2 之间的关系。CXCL12 以剂量依赖的方式诱导人星形胶质细胞中的 COX-2 和 PGE2 的分泌。用百日咳毒素和 AMD3100 处理可消除这种诱导，证实了 CXCR4 信号的作用。通过使用吡咯烷二硫代氨基甲酸盐和瞬时转染实验证实了核因子-κB 的参与。核因子-κB 抑制蛋白的过表达消除了 COX-2 的诱导，并且 CXCL12 诱导了 p65/relA 易位。用 CXCL12 处理的星形胶质细胞的培养上清液降低了神经母细胞瘤细胞的活力，而 COX 抑制剂消除了这种毒性。因此，趋化因子和 PG 之间的关系可能会对导致神经退行性变的致病网络产生不同的影响。
