TAK1-mediated induction of nitric oxide synthase gene expression in glial cells
TAK1-mediated induction of nitric oxide synthase gene expression in glial cells
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DOI：
10.1046/j.1471-4159.2003.01998.x
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发表时间：
2003-10-01
影响因子：
4.7
通讯作者：
Fan, F
中科院分区：
文献类型：
--
作者：
Bhat, NR;Shen, Q;Fan, F
导致转录激活的炎性细胞信号传导主要由通过丝裂原活化蛋白激酶（MAPK）和NF κ B途径的信号转导介导。发出这些途径激活信号的常见上游激酶是TGF β激活激酶1（TAK 1），其本身响应于细胞因子并且在参与先天免疫的一类细胞表面受体（即细菌和病毒病原体的Toll样受体（TLR））接合时被激活。本研究直接测试的作用，TAK 1在诱导诱导型一氧化氮（NO）合酶（iNOS）的神经胶质细胞，这代表免疫调节细胞的中枢神经系统，通过瞬时转染试验。C-6胶质细胞，原代星形胶质细胞和大鼠小胶质细胞系与TAK 1（但不是其失活形式）沿着激活蛋白，TAK 1结合蛋白1（TAB 1）的转染导致在一个显着的刺激共转染大鼠iNOS启动子-报告构建体（iNOS-Luc）。TAK 1诱导的iNOS-Luc活性基本上被已知下游激酶p38 MAPK和JNK（SB 203580和SP 620125）的药理学抑制剂抑制，并且几乎被IkappaB的磷酸化突变体的共表达完全阻断。TAK 1/TAB 1还以p38 MAPK、JNK和NF κ B依赖的方式诱导小胶质细胞NO的产生和iNOS的表达。这些研究的结果提供了证据TAK 1介导的细胞内信号转导，通过p38 MAPK，JNK和NF κ B，在神经胶质细胞中的iNOS的转录激活的重要作用。
Inflammatory cell signaling leading to transcriptional activation is primarily mediated by signal transduction via mitogen-activated protein kinase (MAPK) and NFkappaB pathways. A common upstream kinase that signals the activation of these pathways is TGFbeta-activated kinase 1 (TAK1), which itself becomes activated in response to cytokines and upon engagement of a class of cell surface receptors involved in innate immunity, that is Toll-like receptors (TLRs) by bacterial and viral pathogens. This study directly tests the role of TAK1 in the induction of inducible nitric oxide ( NO) synthase ( iNOS) in glial cells, which represent immune-regulatory cells of the CNS, by transient transfection assays. Transfection of C-6 glia, primary astrocytes and a rat microglial cell line with TAK1 ( but not its inactive form) along with its activator protein, TAK1-binding protein 1 ( TAB1) resulted in a marked stimulation of a co-transfected rat iNOS promoter-reporter construct (iNOS-Luc). TAK1-induced iNOS-Luc activity was substantially inhibited by pharmacological inhibitors of the known downstream kinases, p38 MAPK and JNK (SB203580 and SP620125), and was almost completely blocked by co-expression of a phosphorylation mutant of IkappaB. TAK1/ TAB1 also induced the production of NO and the expression of iNOS in microglial cells in a p38 MAPK-, JNK- and NFkappaB-dependent manner. The results of these studies provide evidence for an important role for TAK1-mediated intracellular signaling, via p38 MAPK, JNK and NFkappaB, in the transcriptional activation of iNOS in glial cells.