Tumor necrosis factor alpha inhibits glutamate uptake by primary human astrocytes - Implications for pathogenesis of HIV-1 dementia
Tumor necrosis factor alpha inhibits glutamate uptake by primary human astrocytes - Implications for pathogenesis of HIV-1 dementia
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DOI：
10.1074/jbc.271.26.15303
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发表时间：
1996-06-28
影响因子：
4.8
通讯作者：
Gelbard, HA
中科院分区：
文献类型：
--
作者：
Fine, SM;Angel, RA;Gelbard, HA
人类免疫缺陷病毒（HIV）感染通常与神经系统疾病相关，这些疾病发生在明显没有HIV广泛感染脑细胞的情况下，这表明中枢神经系统的神经发病机制可能包括星形胶质细胞正常神经保护功能的改变。为了验证这一假设，我们检测了由hiv -1感染的巨噬细胞和小胶质细胞产生的促炎细胞因子肿瘤坏死因子α (TNF α)对人类胎儿星形胶质细胞（PHFAs）转运谷氨酸的影响。在PHFAs中加入外源性重组人TNF α后12-24小时，观察到高亲和力谷氨酸摄取位点的剂量依赖性抑制。这种效果是特异性的，因为它被一种针对TNF α的中和性单克隆抗体阻断。此外，抑制作用可通过单克隆抗体复制，该抗体是55-kDa TNF受体的激动剂。这些结果表明，TNF α的神经毒性作用可能部分是由于其抑制星形胶质细胞摄取谷氨酸的能力，这反过来可能导致突触中谷氨酸的兴奋毒性浓度。
Human immunodeficiency virus (HIV) infection is commonly associated with neurological disease that occurs in the apparent absence of extensive infection of brain cells by HIV, suggesting that indirect mechanisms account for neuropathogenesis in the CNS, perhaps including changes in the normal neuroprotective functions of astrocytes. To test this hypothesis, we examined the effect of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), produced by HIV-1-infected macrophages and microglia, on glutamate transport by primary human fetal astrocytes (PHFAs). A dose-dependent inhibition of high affinity glutamate uptake sites was observed 12-24 h after addition of exogenous recombinant human TNF alpha to PHFAs. This effect was specific since it was blocked by a neutralizing monoclonal antibody directed against TNF alpha. Furthermore, the inhibitory effect was reproduced by a monoclonal antibody that is an agonist at the 55-kDa TNF receptor. These results suggest that the neurotoxic effects of TNF alpha may be due in part to its ability to inhibit glutamate uptake by astrocytes, which in turn may result in excitotoxic concentrations of glutamate in synapses.