Potential dengue virus-triggered apoptotic pathway in human neuroblastoma cells:: Arachidonic acid, superoxide anion, and NF-κB are sequentially involved
Potential dengue virus-triggered apoptotic pathway in human neuroblastoma cells:: Arachidonic acid, superoxide anion, and NF-κB are sequentially involved
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DOI：
10.1128/jvi.74.18.8680-8691.2000
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发表时间：
2000-09-01
影响因子：
5.4
通讯作者：
Shaio, MF
中科院分区：
文献类型：
--
作者：
Jan, JT;Chen, BH;Shaio, MF
人体神经细胞对登革病毒易感性的直接体内证据尚未报道。在这项研究中，我们证明，2型登革病毒（DEN-2）感染诱导广泛的人神经母细胞瘤细胞系SK-N-SH细胞凋亡。DEN-2感染后，磷脂酶A（2）（PLA（2））被激活，导致花生四烯酸（AA）的产生。PLA（2）抑制剂AACOCF（3）和ONO-RS-082抑制PLA（2）活性可减少DEN-2病毒诱导的细胞凋亡。相反，环氧合酶抑制剂阿司匹林和吲哚美辛，认为通过阻断AA catalysts增加AA的积累，增强细胞凋亡。外源性AA以剂量依赖方式诱导细胞凋亡。超氧阴离子被认为是通过AA激活的NADPH氧化酶产生的，在感染后增加。用超氧化物歧化酶（SOD）预处理可保护细胞免受DEN-2病毒诱导的凋亡。此外，AACOCF（3）可阻断超氧阴离子的产生。另外，DEN-2病毒感染后，转录因子NF-κ B和c-Jun被激活。然而，用含有NF-κ B B而非c-Jun结合位点（转录因子诱饵）的寡脱氧核苷酸预处理细胞强烈阻止了登革病毒诱导的细胞凋亡。AACOCF（3）和SOD显著阻断NF-κ B B的活化，这一发现表明这种活化来自AA-超氧阴离子途径。我们的研究结果表明，DEN-2病毒感染人神经母细胞瘤细胞通过激活PLA（2），产生超氧阴离子，随后激活NF-κ B B，触发凋亡途径。这种凋亡作用可以直接来源于AA和超氧阴离子对线粒体的作用，也可以间接来源于NF-κ B B激活的凋亡相关基因的产物。
Direct in vivo evidence for the susceptibility of human neuronal cells to dengue virus has not been reported. In this study, we demonstrated that type 2 dengue (DEN-2) virus infection induced extensive apoptosis in the human neuroblastoma cell line SK-N-SH. Phospholipase A(2) (PLA(2)) was activated by DEN-2 infection, which led to the generation of arachidonic acid (AA). Inhibition of PLA(2) activity by the PLA(2) inhibitors, AACOCF(3) and ONO-RS-082, diminished DEN-2 virus-induced apoptosis. In contrast, the cyclooxygenase inhibitors aspirin and indomethacin, thought to increase AA accumulation by blocking AA catabolism, enhanced apoptosis. Exogenous AA induced apoptosis in a dose-dependent manner. Superoxide anion, which is thought to be generated through the AA-activated NADPH oxidase, was increased after infection. Pretreatment with superoxide dismutase (SOD) protected cells against DEN-2 virus-induced apoptosis. Furthermore, generation of superoxide anion was blocked by AACOCF(3). In addition, the transcription factors, NF-kappa B and c-Jun, were found to be activated after DEN-2 virus infection. However, pretreatment of cells with oligodeoxynucleotides containing NF-kappa B, but not c-Jun, binding sites (transcription factor decoy) strongly prevented dengue virus-induced apoptosis. The finding that AACOCF(3) and SOD significantly block activation of NF-kappa B suggests that this activation is derived from the AA-superoxide anion pathway. Our results indicate that DEN-2 virus infection of human neuroblastoma cells triggers an apoptotic pathway through PLA(2) activation to superoxide anion generation and subsequently to NF-kappa B activation. This apoptotic effect can be either directly derived from the action of AA and superoxide anion on mitochondria or indirectly derived from the products of apoptosis-related genes activated by NF-kappa B.