Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson's disease
Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson's disease
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DOI：
10.1111/j.1460-9568.2003.03014.x
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发表时间：
2003-11-01
影响因子：
3.4
通讯作者：
Oertel, WH
中科院分区：
文献类型：
--
作者：
Depino, AM;Earl, C;Oertel, WH
小胶质细胞活化与帕金森病（PD）的发病机制有关。在该反应的许多组分中，细胞因子已被提出作为介导神经变性或神经保护作用的候选物。我们研究了白细胞介素-1系统和肿瘤坏死因子-α mRNA和蛋白水平在不同的时间间隔在亚急性纹状体内6-羟基多巴胺大鼠模型的PD，在平行的炎症反应。免疫组化结果显示，黑质白质内的小胶质细胞在损伤后6-30天被激活。这种小胶质细胞活化伴随着非典型促炎细胞因子的产生：在6-羟基多巴胺注射后30天，发现白细胞介素-1 α和β mRNA升高（分别为2倍和16倍），但ELISA未检测到蛋白水平的白细胞介素-1 α或β诱导。作为对照，经典的促炎刺激，即内毒素，能够诱导这些细胞因子在类似的mRNA水平，但也在蛋白质水平。此外，在研究的任何时间点，在黑质中几乎未检测到或未检测到肿瘤坏死因子α mRNA。我们的数据指出，在我们的PD模型中，关键的促炎细胞因子的产生受到严格控制。这项工作支持的概念，慢性神经元死亡本身并不诱导这些促炎细胞因子的分泌，但额外的刺激是必要的刺激促炎细胞因子的产生。如最近在朊病毒疾病模型中提出的，从“引发的”小胶质细胞产生促炎细胞因子可以反过来调节疾病进展。
Microglial activation has been associated with the pathogenesis of Parkinson's disease (PD). Among the many components of this reaction, cytokines have been proposed as candidates to mediate neurodegenerative or neuroprotective effects. We investigated the interleukin-1 system and tumour necrosis factor-alpha mRNA and protein levels at different time intervals in the subacute intrastriatal 6-hydroxydopamine rat model of PD, in parallel with the inflammatory response. Immunohistochemistry showed that microglial cells were activated from days 6-30 postlesion in the substantia nigra pars compacta. This microglial activation was accompanied by an atypical proinflammatory cytokine production: Interleukin-1alpha and beta mRNAs were found to be elevated 30 days post-6-hydroxydopamine injection (2- and 16-fold, respectively), but no induction for interleukin-1alpha or beta at the protein level was detected by ELISA. As a control, a classical proinflammatory stimulus, namely endotoxin, was capable of inducing these cytokines at similar mRNA levels but also at the protein level. In addition, tumour necrosis factor-alpha mRNA was hardly or not detected in the substantia nigra at any time point studied. Our data point out a tight control of key proinflammatory cytokine production in our model of PD. This work supports the notion that chronic neuronal death per se does not induce secretion of these proinflammatory cytokines but that an additional stimulus is necessary to stimulate proinflammatory cytokine production. The production of proinflammatory cytokines from "primed" microglia may in turn modulate disease progression as has been recently proposed in a model of prion disease.