Tumour necrosis factor-induced death of adult human oligodendrocytes is mediated by apoptosis inducing factor
Tumour necrosis factor-induced death of adult human oligodendrocytes is mediated by apoptosis inducing factor
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DOI：
10.1093/brain/awh627
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发表时间：
2005-11-01
期刊：
影响因子：
14.5
通讯作者：
Selmaj, K
中科院分区：
文献类型：
--
作者：
Jurewicz, A;Matysiak, M;Selmaj, K
肿瘤坏死因子 (TNF) 诱导的少突胶质细胞死亡，少突胶质细胞是多发性硬化症的靶细胞类型，由 TNF 受体 p55 (TNFR-p55) 介导。 TNFR-p55 的连接诱导多种信号转导途径；然而，人类少突胶质细胞（hOL）死亡的确切机制尚不清楚。我们定义 TNF 诱导的 hOL 死亡是非半胱天冬酶依赖性的，这一点可以通过缺乏半胱天冬酶 8、1 和 3 活性亚基的产生来证明；缺乏半胱天冬酶 1 和 3 荧光底物的裂解；且缺乏通用 caspase 抑制剂 ZVAD.FMK 的 hOL 死亡抑制作用。 TNF 暴露的 hOL DNA 电泳揭示了凋亡诱导因子 (AIF) 介导的细胞死亡的大规模 DNA 片段化特征，共定位实验表明，暴露于 TNF 后，AIF 易位至细胞核。通过反义策略消除 AIF 可防止 TNF 诱导的 hOL 死亡。这些结果表明 TNF 诱导的 hOL 死亡依赖于 AIF，这一信息对于设计在免疫介导的脱髓鞘过程中保护 hOL 的策略具有重要意义。
Tumour necrosis factor (TNF)-induced death of oligodendrocytes, the cell type targeted in multiple sclerosis, is mediated by TNF receptor p55 (TNFR-p55). The ligation of TNFR-p55 induces several signal transduction pathways; however, the precise mechanism involved in human oligodendrocyte (hOL) death is unknown. We defined that TNF-induced death of hOLs is non-caspase dependent, as evidenced by lack of generation of caspases 8, 1 and 3 active subunits; lack of cleavage of caspases 1 and 3 fluorogenic substrates; and lack of hOL death inhibition by the general caspase inhibitor, ZVAD.FMK. Electrophoresis of TNF-exposed hOL DNA revealed large-scale DNA fragmentation characteristic of apoptosis-inducing factor (AIF)-mediated cell death, and co-localization experiments showed that AIF translocation to the nucleus occurred upon exposure to TNF. AIF depletion by an antisense strategy prevented TNF-induced hOL death. These results indicate that TNF-induced death of hOLs is dependent on AIF, information of significance for the design strategies to protect hOLs during immune-mediated demyelination.