Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus
Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus
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DOI：
10.1002/jnr.1050
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发表时间：
2001-04-01
影响因子：
4.2
通讯作者：
Santoro, TJ
中科院分区：
文献类型：
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作者：
Tomita, M;Holman, BJ;Santoro, TJ
系统性红斑狼疮(SLE)是一种病因不明的自身免疫性疾病，约60%的患者伴有中枢神经系统受累。本研究以MRL-lpr/lpr小鼠为实验模型，记录了SLE小脑功能障碍的表达。这些小鼠自发地发展出一种具有人类狼疮免疫学和临床特征的疾病。我们发现MRL-LPR/LPR小鼠表现出严重的进行性行为障碍，表明小脑功能障碍始于11周大。虽然已知LPR基因可以诱导自身免疫功能，但免疫正常的LPR基因同源小鼠并未表现出小脑功能障碍。由于狼疮是一种细胞因子驱动的疾病，某些促炎细胞因子的过度表达与神经退行性变有关，因此我们研究了小脑功能障碍与细胞因子基因表达的关系。相对于免疫正常的CBA/J小鼠，年轻(11-15周龄)MRL-LPR/LPR小鼠的小脑中含有高水平的白介素6(IL)-6和干扰素-γ(干扰素-γ)mRNA，这在老年(22-30周龄)自身免疫小鼠中更为明显。与CBA/J相比，老年但不年轻的MRL-LPR/LPR小鼠小脑中细胞因子IL-1β和IL-10的mRNA水平升高。相反，自身免疫组和正常小鼠小脑中IL-3和肿瘤坏死因子-α的转录水平相似，表明IL-6、干扰素-γ、IL-1β和IL-10的基因表达增强是选择性的。这些结果提示某些促炎细胞因子在SLE小脑功能障碍的发病机制中具有潜在的作用。(C)2001年Wiley-Liss，Inc.
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology accompanied by central nervous system involvement in up to 60% of patients. The current study chronicles the expression of cerebellar dysfunction in SLE using MRL-lpr/lpr mice as the experimental model. These mice spontaneously develop an illness that has immunological and clinical features of human lupus. We found that MRL-lpr/lpr mice manifest severe and progressive behavioral disturbances indicative of cerebellar dysfunction beginning at 11 weeks of age. Although the lpr gene is known to induce autoimmune features, immunologically normal mice rendered congenic for lpr failed to exhibit disturbances in cerebellar function. Because lupus is a cytokine-driven disease and overexpression of certain proinflammatory cytokines has been associated with neurodegeneration, the relationship between cerebellar dysfunction and cytokine gene expression was examined. Relative to immunologically normal CBA/J mice, the cerebellum of young (11-15 weeks of age) MRL-lpr/lpr mice contained high levels of interleukin (IL)-6 and interferon-gamma (IFN gamma) mRNA, which became even more pronounced in old (22-30 weeks of age) autoimmune mice. mRNA levels for the cytokines IL-1 beta and IL-10 were elevated in the cerebellum of old, but not young, MRL-lpr/lpr mice relative to CBA/J. In contrast, the levels of cerebellar transcripts for IL-3 and tumor necrosis factor-alpha were comparable in autoimmune and normal mice, indicating that enhanced gene expression of IL-6, IFN gamma, IL-1 beta, and IL-10 was selective. These results suggest a potential role for certain proinflammatory cytokines in the pathogenesis of cerebellar disturbances in SLE. (C) 2001 Wiley-Liss, Inc.