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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >NF-kappaB mediates MPP+-induced apoptotic cell death in neuroblastoma cells SH-EP1 through JNK and c-Jun/AP-1.
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NF-kappaB mediates MPP+-induced apoptotic cell death in neuroblastoma cells SH-EP1 through JNK and c-Jun/AP-1.

机译：NF-κB通过JNK和c-Jun / AP-1介导MPP +诱导神经母细胞瘤细胞SH-EP1凋亡。

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摘要

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in substantia nigra with unknown etiology. Neuropathology seen in the brains of PD patients can be closely mimicked by MPP(+)-induced neurotoxicity in vitro. In this study, we used an S-type human neuroblastoma cell line (SH-EP1) as a model to investigate the involvement of NF-kappaB and JNK pathways in MPP(+)-induced neurotoxicity. We show that NF-kappaB was activated by MPP(+) as evidenced by NF-kappaB p65 nuclear translocation, the increased DNA binding activity and a rapid phosphorylation of NF-kappaB inhibitor (IkappaBalpha). NF-kappaB partially mediated the neurotoxicity of MPP(+), as suggested by the reduction of MPP(+)-induced cell death by both a specific IkappaB kinase (IKK) inhibitor and a dominant negative form of IkappaBalpha (IkappaBalpha-M). Besides NF-kappaB, JNK and c-Jun/AP-1 were also activated upon MPP(+) stimulation. Inhibition of JNK activation with a specific JNK inhibitor partially reduced the MPP(+)-mediated cell death. Similarly, inhibition of c-Jun/AP-1 activation, either by a dominant negative c-Jun or c-Jun/AP-1 inhibitor, significantly attenuated MPP(+)-mediated cell death. These results suggest that both JNK and c-Jun/AP-1 activation are pro-apoptotic. Furthermore, we provide clear evidence for the existence of a crosstalk between the NF-kappaB and JNK signaling as MPP(+)-induced activation of JNK and c-Jun/AP-1 was strongly down-regulated in IkappaBalpha-M cells. In conclusion, we demonstrate that in SH-EP1 cells MPP(+)-induced neurotoxicity is partially mediated by NF-kappaB which in turn acts on the activation of JNK and c-Jun/AP-1. These results may point to a combined inhibition of NF-kappaB and JNK as a new approach to PD therapy.
机译：帕金森氏病（PD）的特征是病因不明的黑质中多巴胺能神经元的进行性丧失。在PD患者的大脑中看到的神经病理学可以被MPP（+）诱导的体外神经毒性紧密地模仿。在这项研究中，我们使用了S型人类神经母细胞瘤细胞系（SH-EP1）作为模型，以研究NF-κB和JNK通路在MPP（+）诱导的神经毒性中的参与。我们显示，NF-kappaB被MPP（+）激活，如NF-kappaB p65核易位，增加的DNA结合活性和NF-kappaB抑制剂（IkappaBalpha）的快速磷酸化所证明。 NF-kappaB部分介导了MPP（+）的神经毒性，这是由特定的IkappaB激酶（IKK）抑制剂和IkappaBalpha（IkappaBalpha-M）的显性阴性形式降低MPP（+）诱导的细胞死亡所暗示的。除NF-κB外，JNK和c-Jun / AP-1在MPP（+）刺激后也被激活。用特定的JNK抑制剂抑制JNK激活部分减少了MPP（+）介导的细胞死亡。同样，显性阴性c-Jun或c-Jun / AP-1抑制剂对c-Jun / AP-1激活的抑制作用显着减弱了MPP（+）介导的细胞死亡。这些结果表明，JNK和c-Jun / AP-1激活均具有促凋亡作用。此外，我们为NF-kappaB和JNK信号之间存在串扰提供了明确的证据，因为在IkappaBalpha-M细胞中MPP（+）诱导的JNK和c-Jun / AP-1激活被强烈下调。总之，我们证明在SH-EP1细胞中，MPP（+）诱导的神经毒性部分由NF-κB介导，而NF-κB反过来又对JNK和c-Jun / AP-1的激活起作用。这些结果可能表明联合抑制NF-κB和JNK是PD治疗的一种新方法。

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