Interferon-γ protects against cuprizone-induced demyelination
Interferon-γ protects against cuprizone-induced demyelination
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DOI：
10.1006/mcne.2000.0883
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发表时间：
2000-10-01
影响因子：
3.5
通讯作者：
Popko, B
中科院分区：
文献类型：
--
作者：
Gao, X;Gillig, TA;Popko, B
有证据表明，干扰素-γ（IFN-γ），一种由活化的T淋巴细胞分泌的促炎细胞因子，对免疫介导的脱髓鞘疾病如多发性硬化症和实验性自身免疫性脑脊髓炎（EAE）产生有害作用。然而，当编码IFN-γ或其受体的基因突变时，通常对EAE诱导具有抗性的小鼠品系变得易感，这表明这种细胞因子在脱髓鞘疾病中起的作用是复杂的。我们研究了IFN-γ在化学诱导的CNS脱髓鞘模型中的作用。通过饮食接受铜螯合剂铜腙的小鼠显示出胼胝体的广泛脱髓鞘。值得注意的是，在CNS中异位表达低水平IFN-γ的转基因小鼠在用cuprizone治疗时没有显示脱髓鞘的证据，它们也没有显示少突胶质细胞死亡、星形胶质细胞增生或小胶质细胞增生的迹象，这通常在治疗的动物中看到。然而，髓鞘蛋白基因的表达显着减少，在治疗的控制和转基因动物，表明脱髓鞘是不是一个强制性的后果髓鞘蛋白合成的大幅减少。有趣的是，表达IFN-γ的小鼠的CNS含有升高水平的胰岛素样生长因子I，其已被证明对铜腙的脱髓鞘作用具有保护作用。
Evidence suggests that interferon-gamma (IFN-gamma), a proinflammatory cytokine secreted by activated T lymphocytes, contributes a deleterious effect to immune-mediated demyelinating disorders such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Nevertheless, mouse strains that are normally resistant to EAE induction become susceptible when the gene encoding either IFN-gamma or its receptor is mutated, demonstrating that the role that this cytokine plays in demyelinating disorders is complex. We have examined the effect of IFN-gamma in a chemically induced model of CNS demyelination. Mice that receive through their diet the copper chelator cuprizone display extensive demyelination of the corpus callosum. Remarkably, transgenic mice that ectopically express low levels of IFN-gamma in the CNS did not display evidence of demyelination when treated with cuprizone, nor did they shows signs of oligodendroglial death, astrogliosis, or microgliosis, which are typically seen in treated animals. Myelin protein gene expression was, however, dramatically reduced in both the treated control and the transgenic animals, indicating that demyelination is not an obligatory consequence of a large diminution of myelin protein synthesis. Interestingly, the CNS of the IFN-gamma -expressing mice contained elevated levels of insulin-like growth factor I, which has been demonstrated to have a protective effect against the demyelinating action of cuprizone.