Metallothioneins are upregulated in symptomatic mice with astrocyte-targeted expression of tumor necrosis factor-alpha.
Metallothioneins are upregulated in symptomatic mice with astrocyte-targeted expression of tumor necrosis factor-alpha.
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在星形胶质细胞靶向表达肿瘤坏死因子-α 的有症状小鼠中，金属硫蛋白上调。
DOI：
10.1006/exnr.1999.7335
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Hidalgo,J
中科院分区：
文献类型：
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作者：
Carrasco,J;Giralt,M;Penkowa,M;Stalder,AK;Campbell,IL;Hidalgo,J
在GFAP基因启动子调控下表达TNF-α的转基因小鼠（GFAP-TNF -α小鼠）表现出独特的迟发性慢性进行性神经系统疾病，包括脑膜脑脊髓炎、神经退行性变性和脱髓鞘并瘫痪。在这里，我们发现尽管在两种情况下都存在TNF-α表达，但在症状性而非症状前gfap -TNF -α小鼠的大脑中，金属硫蛋白- i + II （MT-I + II）亚型显著上调。MT-I RNA的原位杂交分析和MT-I + II蛋白的放射免疫分析结果显示，在小脑中观察到诱导，而在其他脑区没有。MT-I RNA水平升高发生在小脑浦肯野和颗粒神经元层，但也发生在分子层。活性星形胶质细胞，活化的杆状小胶质细胞和巨噬细胞，而不是浸润的淋巴细胞，被确定为MT-I + II蛋白的细胞来源。MT-III RNA原位杂交显示小脑白质适度增加，免疫细胞化学证实了这一点。MT-III免疫反应性主要存在于圆形或变形虫单核细胞/巨噬细胞中。不同MT亚型在gmap - tnf - α小鼠中的表达模式与之前在gmap - il - 6小鼠中的表达模式有很大不同，表明每种细胞因子的表达具有独特的作用。结果表明，MT在中枢神经系统中的表达反映了炎症反应和相关损伤，而不是TNF-α在其调节中的直接作用，并支持这些蛋白在中枢神经系统损伤中的主要作用。
Transgenic mice expressing TNF-α under the regulatory control of the GFAP gene promoter (GFAP-TNFα mice) exhibit a unique, late-onset chronic-progressive neurological disorder with meningoencephalomyelitis, neurodegeneration, and demyelination with paralysis. Here we show that the metallothionein-I + II (MT-I + II) isoforms were dramatically upregulated in the brain of symptomatic but not presymptomatic GFAP-TNFα mice despite TNF-α expression being present in both cases. In situ hybridization analysis for MT-I RNA and radioimmunoassay results for MT-I + II protein revealed that the induction was observed in the cerebellum but not in other brain areas. Increased MT-I RNA levels occurred in the Purkinje and granular neuronal layers of the cerebellum but also in the molecular layer. Reactive astrocytes, activated rod-like microglia, and macrophages, but not the infiltrating lymphocytes, were identified as the cellular sources of the MT-I + II proteins. In situ hybridization for MT-III RNA revealed a modest increase in the white matter of the cerebellum, which was confirmed by immunocytochemistry. MT-III immunoreactivity was present in cells which were mainly round or amoeboid monocytes/macrophages. The pattern of expression of the different MT isoforms in the GFAP-TNFα mice differed substantially from that described previously in GFAP-IL6 mice, demonstrating unique effects associated with the expression of each cytokine. The results suggest that the MT expression in the CNS reflects the inflammatory response and associated damage rather than a direct role of the TNF-α in their regulation and support a major role of these proteins during CNS injury.