Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-gamma.
Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-gamma.
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DOI：
10.1083/jcb.200502086
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发表时间：
2005-05-23
期刊：
影响因子：
--
通讯作者：
Popko B
中科院分区：
文献类型：
--
作者：
Lin W;Harding HP;Ron D;Popko B
干扰素-γ被认为通过靶向产生髓鞘的少突胶质细胞而导致免疫介导的脱髓鞘疾病，少突胶质细胞对蛋白质合成的中断和分泌途径的干扰高度敏感。我们发现干扰素-γ诱导培养的大鼠少突胶质细胞的凋亡与内质网应激有关。在中枢神经系统不适当表达干扰素-γ的转基因小鼠中，内质网应激还伴随着少突胶质细胞的凋亡和低髓鞘形成。与野生型遗传背景相比，在胰腺ER激酶(PERK)功能突变杂合子小鼠中强制表达干扰素-γ显著降低了动物的存活率，促进了中枢神经系统髓鞘抑制，并增加了少突胶质细胞的丢失。PERK编码一种内质网应激诱导蛋白，使真核细胞翻译起始因子2α磷酸化，并在应激状态下特异性地维持客户蛋白的动态平衡。因此，PERK+/−小鼠对干扰素-γ的超敏反应与中枢神经系统炎症诱导的脱髓鞘障碍中的内质网应激有关。
I*nterferon-γ (IFN-γ) is believed to contribute to immune-mediated demyelinating disorders by targeting the myelin-producing oligodendrocyte, a cell known to be highly sensitive to the disruption of protein synthesis and to the perturbation of the secretory pathway. We found that apoptosis induced by IFN-γ in cultured rat oligodendrocytes was associated with endoplasmic reticulum (ER) stress. ER stress also accompanied oligodendrocyte apoptosis and hypomyelination in transgenic mice that inappropriately expressed IFN-γ in the central nervous system (CNS). Compared with a wild-type genetic background, the enforced expression of IFN-γ in mice that were heterozygous for a loss of function mutation in pancreatic ER kinase (PERK) dramatically reduced animal survival, promoted CNS hypomyelination, and enhanced oligodendrocyte loss. PERK encodes an ER stress–inducible kinase that phosphorylates eukaryotic translation initiation factor 2α and specifically maintains client protein homeostasis in the stressed ER. Therefore, the hypersensitivity of PERK+/− mice to IFN-γ implicates ER stress in demyelinating disorders that are induced by CNS inflammation.
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