Suppressor of cytokine signaling 1 expression protects oligodendrocytes from the deleterious effects of interferon-γ
Suppressor of cytokine signaling 1 expression protects oligodendrocytes from the deleterious effects of interferon-γ
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DOI：
10.1523/jneurosci.0737-06.2006
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发表时间：
2006-05-10
影响因子：
5.3
通讯作者：
Popko, Brian
中科院分区：
文献类型：
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作者：
Balabanov, Roumen;Strand, Krystal;Popko, Brian
干扰素-γ是一种由T细胞和自然杀伤细胞产生的多效性细胞因子，已被认为是免疫介导性脱髓鞘疾病多发性硬化症的有害因子。在体外，纯化的发育中的少突胶质细胞和成熟的少突胶质细胞在干扰素-γ的存在下分别通过凋亡和坏死而死亡。此外，在发育过程中转基因表达的小鼠中枢神经系统会导致震颤、髓鞘减少和少突胶质细胞丢失，而成年动物在脱髓鞘损伤后表达干扰素-γ会抑制再髓鞘形成。为了研究干扰素-γ诱导的少突胶质细胞损伤的分子机制，我们建立了一个转基因小鼠系[PLP/SOCS1(蛋白质脂蛋白/细胞因子信号抑制因子1)]，该系小鼠由于在这些细胞中靶向表达SOCS1而表现出对干扰素-γ的反应减弱。我们证明了PLP/SOCS1转基因小鼠的少突胶质细胞可以抵抗干扰素-γ的损伤效应。我们的数据表明，干扰素-γ对发育中的少突胶质细胞具有直接的有害作用。SOCS1抑制干扰素-γ效应的能力提示了一种保护髓鞘少突胶质细胞免受炎症有害影响的治疗方法。
Interferon-gamma( IFN-gamma) is a pleiotropic cytokine produced by T cells and natural killer cells that has been implicated as a deleterious factor in the immune-mediated demyelinating disorder multiple sclerosis. In vitro, purified developing and mature oligodendrocytes have been shown to die in the presence of IFN-gamma by apoptosis and necrosis, respectively. Moreover, transgenic expression of IFN-gamma in the CNS of mice during development results in tremor, hypomyelination, and oligodendrocyte cell loss, and IFN-gamma expression in adult animals after demyelinating insults inhibits remyelination. To examine the molecular mechanisms of IFN-gamma-induced oligodendrocyte injury, we generated a transgenic mouse line [PLP/SOCS1 (proteolipid protein/suppressor of cytokine signaling 1)] that exhibits diminished oligodendrocyte responsiveness to IFN-gamma attributable to the targeted expression of SOCS1 in these cells. We demonstrate that oligodendrocytes in the PLP/SOCS1 transgenic mice are protected against the injurious effect of IFN-gamma. Our data indicate that IFN-gamma exerts a direct deleterious effect on developing oligodendrocytes. The capacity of SOCS1 to inhibit the effects of IFN-gamma suggests a therapeutic approach toward protection of myelinating oligodendrocytes against the harmful effects of inflammation.