Role of cytokines in inflammatory process in Parkinson's disease.
Role of cytokines in inflammatory process in Parkinson's disease.
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DOI：
10.1007/978-3-211-45295-0_57
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发表时间：
2006
期刊：
影响因子：
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通讯作者：
M. Sawada;K. Imamura;T. Nagatsu;T. Nagatsu
中科院分区：
文献类型：
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作者：
M. Sawada;K. Imamura;T. Nagatsu;T. Nagatsu
我们研究了在散发性帕金森病（PD）中黑质（SN）和壳核中活化的小胶质细胞中产生的细胞因子是否具有神经保护作用或神经毒性。在PD的尸检脑中，在PD的进展过程中，在SN和壳核中，MHC II类（CR 3/43）阳性活化的小胶质细胞的数量增加，这些小胶质细胞也是ICAM-1（CD 54）-、LFA-1（CD 11 a）-、TNF-α-和IL-6阳性的。在早期阶段，活化的小胶质细胞主要与壳核中的酪氨酸羟化酶（TH）阳性神经突起相关，在晚期阶段，与SN中受损的TH阳性神经元相关。PD患者的小胶质细胞不仅在黑质-纹状体区，而且在海马和大脑皮层等脑区也有激活。我们研究了PD和Lewy小体病（LBD）海马中活化小胶质细胞的分布以及细胞因子和神经营养因子的表达。IL-6和TNF-α mRNA的水平在PD和LBD中均增加，但BDNF mRNA和蛋白的水平在LBD中显著降低，其中不仅在黑质纹状体而且在海马中观察到神经元损失。结果表明，在PD中，海马中激活的小胶质细胞可能具有神经保护作用，而在LBD中，这些小胶质细胞可能具有神经毒性。作为支持这一假设的证据，通过细胞分选从小鼠脑中分离出两个小胶质细胞亚群：一个亚群具有高活性氧（ROS）产生，另一个亚群不产生ROS。当与神经元细胞共培养时，一个具有高ROS产生的小胶质细胞克隆具有神经毒性，但另一个没有ROS产生的克隆具有神经保护作用。另一方面，Sawada及其同事发现，通过转导具有增加的NADPH氧化酶活性的HIV-1 Nef蛋白，培养实验中的神经保护性小胶质细胞克隆转化为毒性小胶质细胞克隆。两者合计，所有这些结果表明，激活的小胶质细胞可能会改变在体内从神经保护的神经毒性亚组的多巴胺神经元的变性在SN进展PD。结论：黑质和壳核内活化的小胶质细胞释放的细胞因子在PD发病初期可能具有神经保护作用，但在PD进展过程中可能具有神经毒性作用，在Alzheimer病等伴有炎症的神经退行性疾病中也可能发生活化的小胶质细胞毒性改变。
We investigated whether the cytokines produced in activated microglia in the substantia nigra (SN) and putamen in sporadic Parkinson’s disease (PD) are neuroprotective or neurotoxic. In autopsy brains of PD, the number of MHC class II (CR3/43)-positive activated microglia, which were also ICAM-1 (CD 54)-, LFA-1 (CD 11a)-, TNF-alpha-, and IL-6-positive, increased in the SN and putamen during progress of PD. At the early stage activated microglia were mainly associated with tyrosine hydroxylase (TH)-positive neurites in the putamen, and at the advanced stage with damaged TH-positive neurons in the SN. The activated microglia in PD were observed not only in the nigro-striatal region, but also in various brain regions such as the hippocampus and cerebral cortex. We examined the distribution of activated microglia and the expression of cytokines and neurotrophins in the hippocampus of PD and Lewy body disease (LBD). The levels of IL-6 and TNF-alpha mRNAs increased both in PD and LBD, but those of BDNF mRNA and protein drastically decreased specifically in LBD, in which neuronal loss was observed not only in the nigrostriatum but also in the hippocampus. The results suggest activated microglia in the hippocampus to be probably neuroprotective in PD, but those to be neurotoxic in LBD. As an evidence supporting this hypothesis, two subsets of microglia were isolated from mouse brain by cell sorting: one subset with high production of reactive oxygen species (ROS) and the other with no production of ROS. When co-cultured with neuronal cells, one microglia clone with high ROS production was neurotoxic, but another clone with no ROS production neuroprotective. On the other hand, Sawada with coworkers found that a neuroprotective microglial clone in a culture experiment converted to a toxic microglial clone by transduction of the HIV-1 Nef protein with increasing NADPH oxidase activity. Taken together, all these results suggest that activated microglia may change in vivo from neuroprotective to neurotoxic subtsets as degeneration of dopamine neurons in the SN progresses in PD. We conclude that the cytokines from activated microglia in the SN and putamen may be initially neuroprotective, but may later become neurotoxic during the progress of PD.Toxic change of activated microglia may also occur in Alzheimer’s disease and other neurodegenerative diseases in which inflammatory process is found.