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Molecular Pharmacological studies on the neuron/glia network

神经元/神经胶质网络的分子药理学研究

基本信息

批准号：
06454595
负责人：
NOMURA Yasuyuki
金额：
$ 4.61万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

Nitric oxide (NO) is believed to be involved in neurotoxicity after various neuronal stresses and in synaptic plasticity in the cerebellum and thehippocampus in the central nervous system. In the brain, a constitutively expressed NO synthase (cNOS) is expressed in specific neuronal populations, whereit can act as mentioned above. On the other hand, another type of NOS,inducible NOS (iNOS) , is induced by treatment with bacterial endotoxin (lipopolysaccharide, LPS) and/or cytokines in brainglial cells. However, the signal transduction system responsible for induction of iNOS is poorly understood. We examined the induction mechanism of iNOS stimulated by LPS plus interferon-gamma(IFN-gamma) in C6 glioma cells. LPS or IFN-gamma alone could not induce iNOS,but combination of LPS plus IFN-gamma markedly induced iNOS in C6 glioma sells. We found that pretreatment with herbimycin A,apotent selective tyrosine kinase inhibitor, suppressed the induction of NOS by LPS plus IFN-gamma. LPS activated NF-kBand this effect was also sensitive to herbimycin A.On the other hand, IFN-gammastimulated tyrosine-phosphorylation ofJAK2 and STAT1alpha and translocation of STAT1alphato nuclei. These activation by IFN-gamma was also inhibited by herbimycin A.Taken together, these findings suggestthat dual signal transduction pathwaysare required to induce NOS in C6 glioma cells and a tyrosine-kinase is involved in the NF-kB activation.

一氧化氮（NO）被认为参与各种神经元应激后的神经毒性以及中枢神经系统小脑和海马的突触可塑性。在大脑中，一种组成性表达的NO合成酶（cNOS）在特定的神经元群中表达，在那里它可以发挥上述作用。另一方面，另一种类型的NOS，诱导型NOS (iNOS)，是由细菌内毒素（脂多糖，LPS）和/或细胞因子在脑细胞中诱导的。然而，对诱导iNOS的信号转导系统了解甚少。我们研究了LPS +干扰素- γ (ifn - γ)在C6胶质瘤细胞中诱导iNOS的机制。单独使用LPS或ifn - γ不能诱导iNOS，但LPS与ifn - γ联合使用可显著诱导C6胶质瘤细胞的iNOS。我们发现，用有效选择性酪氨酸激酶抑制剂herbimycin A预处理可以抑制LPS + ifn - γ对NOS的诱导。LPS激活NF-kBand，这种效应对herbimycin a也很敏感。另一方面，ifn - γ刺激jak2和stat1 α的酪氨酸磷酸化以及stat1 α核的易位。综上所述，这些发现表明，在C6胶质瘤细胞中诱导NOS需要双重信号转导途径，而酪氨酸激酶参与了NF-kB的激活。