Depino Amaicha M, Earl Chris, Kaczmarczyk Elke, Ferrari Carina, Besedovsky Hugo, del Rey Adriana, Pitossi Fernando J, Oertel Wolfgang H
Institute Leloir Foundation-CONICET-University of Buenos Aires, Avenue Patricias Argentinas 435, (1405) Buenos Aires, Argentina.
Eur J Neurosci. 2003 Nov;18(10):2731-42. doi: 10.1111/j.1460-9568.2003.03014.x.
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.
小胶质细胞激活与帕金森病（PD）的发病机制相关。在这一反应的众多组成部分中，细胞因子被认为是介导神经退行性或神经保护作用的候选因素。我们在PD的亚急性纹状体内注射6-羟基多巴胺大鼠模型中，在不同时间间隔研究白细胞介素-1系统以及肿瘤坏死因子-α的mRNA和蛋白质水平，并同时观察炎症反应。免疫组织化学显示，黑质致密部在损伤后第6至30天小胶质细胞被激活。这种小胶质细胞激活伴随着非典型的促炎细胞因子产生：在注射6-羟基多巴胺后30天，白细胞介素-1α和β的mRNA水平升高（分别升高2倍和16倍），但ELISA检测未发现蛋白质水平的白细胞介素-1α或β诱导。作为对照，经典的促炎刺激物，即内毒素，能够在相似的mRNA水平以及蛋白质水平诱导这些细胞因子。此外，在所研究的任何时间点，黑质中几乎未检测到或未检测到肿瘤坏死因子-α的mRNA。我们的数据指出在我们的PD模型中对关键促炎细胞因子产生的严格控制。这项工作支持这样的观点，即慢性神经元死亡本身不会诱导这些促炎细胞因子的分泌，但需要额外的刺激来刺激促炎细胞因子的产生。如最近在朊病毒病模型中所提出的，来自“预激活”小胶质细胞的促炎细胞因子的产生可能反过来调节疾病进展。
