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Role of cytokines in the lesion repair in the central nervous system

细胞因子在中枢神经系统损伤修复中的作用

基本信息

批准号：
09480216
负责人：
MATSUMOTO Yoh
金额：
$ 2.88万
依托单位：
Tokyo Metropolitan Institute for Neuroscience
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09480216/
关键词：
Central nervous system Competitive PCR Cytokine Autoimmune encephalomyelitis Glia STAT In situ hybridization in situ RT-PCR

项目摘要

To know the role of cytokines in the lesion repair process in the central nervous system (CNS), experimental autoimmune encephalomyelitis (EAE) was induced in rats and the level of pro- and anti-inflammatory cytokine mRNA in the central nervous system (CNS) was quantitated by competitive PCR. In EAE, TNF-α and IFN-γ mRNA were detected mainly at the early stage of the disease, while one of anti-inflammatory cytokines, TGF-β1, peaked at the later stage.In the next step, we investigated the kinetics and localization of STAT (signal transducer and activators of transcription) mRNA and protein, which is known as a transducing molecule activated after cytokine binding to the cytokine receptor, in the CNS during autoimmune inflammation. It was demonstrated that STAT4 which was expressed in microglia and probably activated by IL-12 plays a pro-inflammatory role and that STAT3 which was activated throughout the disease course and expressed mainly in astrocytes seems to serve as a transducer of anti-inflammatory signals.Finally, we have performed in situ hybridization to determine the cell that produce the cytokine in the CNS. Since the amount of cytokines in the CNS is low, special care was taken to improve the sensitivity of the probe used in non-radioisotopic hybridization. With this improvement, it was possible to show that microglia express TNF-α while neuron and astrocytes express TGF-β1.Taking all these findings together, the following mechanism of the region repair is suggested. Soon after the infiltration of autoreactive T cells in the CNS, microglia are activated by T cells and secrete pro-inflammatory cytokines such as TNF-α to upregulate T cell function and at the same time stimulate the astrocyte which downregulate the inflammatory processes by secreting anti-inflammatory cytokines including TGF-β. The cytokine network regulated by various types of brain cells is critical for the region repair in the CNS.

为了了解细胞因子在中枢神经系统 (CNS) 病变修复过程中的作用，在大鼠中诱导实验性自身免疫性脑脊髓炎 (EAE)，并通过竞争性 PCR 定量中枢神经系统 (CNS) 中促炎和抗炎细胞因子 mRNA 的水平。在EAE中，TNF-α和IFN-γ mRNA主要在疾病早期检测到，而抗炎细胞因子之一TGF-β1在后期达到峰值。下一步，我们研究了STAT（信号转导和转录激活剂）mRNA和蛋白质的动力学和定位，STAT（信号转导和转录激活剂）mRNA和蛋白质被认为是细胞因子与细胞因子结合后激活的转导分子。自身免疫性炎症期间中枢神经系统中的细胞因子受体。结果表明，在小胶质细胞中表达并可能被IL-12激活的STAT4发挥促炎作用，而在整个病程中激活并主要在星形胶质细胞中表达的STAT3似乎充当抗炎信号的转导器。最后，我们进行了原位杂交以确定中枢神经系统中产生细胞因子的细胞。由于中枢神经系统中细胞因子的含量较低，因此需要特别注意提高非放射性同位素杂交中使用的探针的灵敏度。通过这一改进，可以证明小胶质细胞表达 TNF-α，而神经元和星形胶质细胞表达 TGF-β1。综合所有这些发现，提出了以下区域修复机制。在中枢神经系统中自身反应性T细胞浸润后不久，小胶质细胞被T细胞激活并分泌促炎细胞因子（如TNF-α）以上调T细胞功能，同时刺激星形胶质细胞，星形胶质细胞通过分泌抗炎细胞因子（包括TGF-β）来下调炎症过程。各种脑细胞调节的细胞因子网络对于中枢神经系统区域的修复至关重要。