BK-induced COX-2 expression via PKC-δ-dependent activation of p42/p44 MAPK and NF-κB in astrocytes
BK-induced COX-2 expression via PKC-δ-dependent activation of p42/p44 MAPK and NF-κB in astrocytes
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DOI：
10.1016/j.cellsig.2006.07.006
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发表时间：
2007-02-01
影响因子：
4.8
通讯作者：
Yang, Chuen-Mao
中科院分区：
文献类型：
--
作者：
Hsieh, Hsi-Lung;Wang, Hui-Hsin;Yang, Chuen-Mao
缓激肽（BK）是一种炎症介质，在几种脑损伤和炎症性疾病的区域水平升高。已显示其诱导环氧化酶-2（考克斯-2）表达，其涉及各种细胞类型中的炎症反应。然而，BK诱导星形胶质细胞考克斯-2表达的信号转导机制尚不清楚。首先，RT-PCR和Western blotting分析表明BK诱导了考克斯-2 mRNA和蛋白的表达，而B2 BK受体拮抗剂Hoe 140则抑制了这种表达，表明B-2 BK受体参与其中。BK诱导的考克斯-2表达和PKC-δ从胞质到膜组分的易位被rottlerin抑制，表明PKC-δ可能参与了这些反应。这一假设进一步得到了PKC-δ显性阴性质粒转染显著阻断BK诱导的考克斯-2表达的支持。BK刺激的p42/p44 MAPK磷酸化、考克斯-2 mRNA表达和前列腺素E-2（PGE（2））释放被PD98059减弱，表明MEK/p42/p44 MAPK参与了该通路。因此，BK刺激的p42/p44 MAPK磷酸化被rottlerin减弱，表明PKC-δ可能是p42/p44 MAPK的上游组分。BK诱导的考克斯-2表达可能是通过NF-κ B B转位入核而实现的，而Helenalin、rottlerin和PD 98059可阻断NF-κ B转位入核，提示NF-κ B参与了BK诱导的COX-2表达。这些结果表明，在RBA-1细胞中，BK诱导的考克斯-2表达和PGE（2）释放依次通过PKC-δ依赖性激活p42/p44 MAPK和NF-κ B B介导。了解BK对星形胶质细胞考克斯-2表达和PGE（2）释放的调控，可能为脑损伤和炎症性疾病的治疗提供新的思路。(c)2006爱思唯尔公司All rights reserved.
Bradykinin (BK) is an inflammatory mediator, elevated levels in the region of several brain injury and inflammatory diseases. It has been shown to induce cyclooxygenase-2 (COX-2) expression implicating in inflammatory responses in various cell types. However, the signaling mechanisms underlying BK-induced COX-2 expression in astrocytes remain unclear. First, RT-PCR and Western blotting analysis showed that BK induced the expression of COX-2 mRNA and protein, which was inhibited by B2BK receptor antagonist Hoe 140, suggesting the involvement of B-2 BK receptors. BK-induced COX-2 expression and translocation of PKC-delta from cytosol to membrane fraction were inhibited by rottlerin, suggesting that PKC-delta might be involved in these responses. This hypothesis was further supported by the transfection with a dominant negative plasmid of PKC-delta significantly blocked BK-induced COX-2 expression. BK-stimulated p42/p44 MAPK phosphorylation, COX-2 mRNA expression, and prostaglandin E-2 (PGE(2)) release were attenuated by PD98059, indicating the involvement of MEK/p42/p44 MAPK in this pathway. Accordingly, BK-stimulated phosphorylation of p42/p44 MAPK was attenuated by rottlerin, indicating that PKC-delta might be an upstream component of p42/p44 MAPK. Moreover, BK-induced COX-2 expression might be mediated through the translocation of NF-kappa B into nucleus which was blocked by helenalin, rottlerin and PD98059, implying the involvement of NF-kappa B. These results suggest that in RBA-1 cells, BK-induced COX-2 expression and PGE(2) release was sequentially mediated through PKC-delta-dependent activation of p42/p44 MAPK and NF-kappa B. Understanding the regulation of COX-2 expression and PGE(2) release induced by BK in astrocytes might provide a new therapeutic strategy of brain injury and inflammatory diseases. (c) 2006 Elsevier Inc. All rights reserved.