Molecular mechanism of psychosine-induced cell death in human oligodendrocyte cell line
Molecular mechanism of psychosine-induced cell death in human oligodendrocyte cell line
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DOI：
10.1046/j.1471-4159.2003.01941.x
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发表时间：
2003-09-01
影响因子：
4.7
通讯作者：
Singh, AK
中科院分区：
文献类型：
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作者：
Haq, E;Giri, S;Singh, AK
本研究揭示了精神病素诱导少突胶质细胞死亡的分子机制。将永生化的人少突胶质细胞系MO3.13用外源性精神病素(P-半乳糖鞘氨醇)处理，这是一种蓄积在Krabbe病患者组织中的有毒代谢物。不同的细胞凋亡标记物TUNEL、DNA片段化和caspase裂解/激活揭示了精神病素诱导的细胞死亡方式。根据线粒体膜电位(A)的变化，精神碱的作用是氧化还原敏感的，这种作用可以被抗氧化剂分子N-乙酰-L-半胱氨酸或原半胱氨酸预先处理而逆转。通过激活caspase9而不是caspase8，神经氨酸直接影响线粒体，上调c-jun/c-jun氨基末端激酶通路导致AP-1的诱导，同时也下调内毒素诱导的核因子-kappaB的反式激活。这些观察表明，精神病素的作用机制是通过上调AP-1，促进细胞凋亡，并通过下调核因子-kappaB途径，抑制细胞凋亡。
This study delineates the molecular mechanism underlying psychosine-induced oligodendroglial cell death. An immortalized human oligodendroglial cell line, MO3.13, was treated with exogenous psychosine (P-galactosylsphingosine), a toxic metabolite that accumulates in the tissues of patients with Krabbe's disease. The mode of cell death induced by psychosine was found to be apoptotic, as revealed by different apoptotic markers viz., TUNEL, DNA fragmentation and caspase cleavage/activation. The action of psychosine was redox sensitive, as measured by changes in mitochondrial membrane potential ( A), and this effect of psychosine could be reversed by pre-treatment with the antioxidant molecules N-acetyl-L-cysteine or pro-cysteine. Psychosine directly affects the mitochondria as revealed by the activation of caspase 9 but not caspase 8. Up-regulation of the c-jun/c-jun N-terminal kinase pathway by psychosine leads to the induction of AP-1 and, at the same time, psychosine also down-regulates the lipopolysaccharide-induced NF-kappaB transactivation. These observations indicate that the mechanism of action of psychosine is, through the up-regulation of AP-1, a pro-apoptotic pathway as well as, through the down-regulation of the NF-kappaB pathway, an antiapoptotic pathway.