Effects of TNF-α and IFN-γ on nitric oxide-induced neurotoxicity in the mouse brain
Effects of TNF-α and IFN-γ on nitric oxide-induced neurotoxicity in the mouse brain
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DOI：
10.4049/jimmunol.172.11.7043
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发表时间：
2004-06-01
影响因子：
4.4
通讯作者：
Rivest, S
中科院分区：
文献类型：
--
作者：
Blais, V;Rivest, S
本研究调查了高活性气态自由基 NO 与活化 Th-1 细胞产生的细胞因子之间对大脑免疫反应和神经元完整性的相互作用。 CD-1小鼠接受纹状体内输注含有NO合酶抑制剂N(G)-硝基-L-精氨酸甲酯、NO释放物质硝普钠(SNP)、IFN-γ和/或TNF-α的不同溶液。含有两种细胞因子的溶液引起输注部位同侧小胶质细胞/单核细胞中编码促炎蛋白的许多基因的深刻且短暂的转录激活。基因表达的增加在细胞因子脑推注后 1 天达到峰值，并在给药后 3 至 7 天恢复到基础水平。 N(G)-硝基-L-精氨酸甲酯进一步刺激了这种针对 IFN-γ 和 TNF-α 的免疫反应，但这些小鼠的大脑未能表现出神经变性和脱髓鞘的迹象。相比之下，纹状体区域的单次 SNP 早在输注 NO 供体后 1 至 3 天就引起神经元死亡和脱髓鞘。尽管TNF-α仍然是增强脑元件损伤的最关键的细胞因子，但两种细胞因子的共同施用大大加剧了这种现象。这些数据证明一氧化氮具有调节免疫反应的能力，而免疫反应本身并不对大脑有害。然而，SNP 诱导的 NO 产生以及大脑环境中的 TNF-α 是导致体内严重神经变性和脱髓鞘的关键事件。
The present study investigated the interaction between highly reactive gaseous-free radical NO and cytokines that are produced by activated Th-1 cells on the cerebral immune response and neuronal integrity. CD-1 mice received an intrastriatal infusion of different solutions containing the NO synthase inhibitor N(G)-nitro-L-arginine methylester, NO-releasing substance sodium nitroprusside (SNP), IFN-gamma, and/or TNF-alpha. The solution containing both cytokines caused a profound and transient transcriptional activation of numerous genes encoding proinflammatory proteins in microglial/monocytic cells ipsilateral to infusion site. This increase in gene expression peaked 1 day after the cerebral bolus of cytokines and returned to basal levels from 3 to 7 days post administration. N(G)-nitro-L-arginine methylester further stimulated this immune reaction to IFN-gamma and TNF-alpha, but the brain of these mice failed to exhibit signs of neurodegeneration and demyelination. In contrast, a single bolus of SNP in the striatal region caused neuronal death and demyelination as early as 1 to 3 days following the infusion with the NO donor. This phenomenon was greatly exacerbated by the coadministration of both cytokines, although TNF-alpha remained the most critical cytokine to enhance the damage of cerebral elements. These data provide evidence that NO has the ability to modulate the immune response, which is not by itself detrimental for the brain. However, SNP-induced NO production together with TNF-alpha in the cerebral environment are critical events leading to intense neurodegeneration and demyelination in vivo.