TLR3 ligation activates an antiviral response in human fetal astrocytes: A role for viperin/cig5
TLR3 ligation activates an antiviral response in human fetal astrocytes: A role for viperin/cig5
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DOI：
10.4049/jimmunol.177.7.4735
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发表时间：
2006-10-01
影响因子：
4.4
通讯作者：
Brosnan, Celia F.
中科院分区：
文献类型：
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作者：
Rivieccio, Mark A.;Suh, Hyeon-Sook;Brosnan, Celia F.
TLR 3作为由dsRNA病毒激活的病毒核酸哨兵和细胞内囊泡内的病毒复制中间体发挥作用。为了探索TLR 3在人星形胶质细胞中诱导的基因谱，我们使用了微阵列方法和类似物聚核糖肌苷酸聚核糖胞苷酸（pIC）作为配体。正如TLR激活所预期的，pIC诱导了广泛的细胞因子和趋化因子，这些细胞因子和趋化因子因其在炎症反应中的作用以及受体本身的上调而闻名。数据还显示了广谱抗病毒反应基因的激活。为了确定pIC是否在星形胶质细胞中诱导抗病毒状态，使用假型HIV病毒颗粒，水泡性口炎病毒g-env-HIV-1。pIC显著消除HIV-1复制，而IL-1，也有效激活星形胶质细胞，没有。在微阵列上最高度上调的基因之一是蛋白质viperin/cig 5。我们发现viperin/cig 5的表达依赖于IFN调节因子3和NF-κ B信号，并且用pIC而不是IL-1重复刺激进一步增加表达。蝰蛇蛋白的诱导也可以被IFN-β的中和抗体实质上抑制，HIV-1的复制也是如此。为了探索蝰蛇蛋白在IFN-β介导的HIV-1抑制中的作用，我们使用了RNA干扰（RNAi）方法。针对蝰蛇蛋白的RNAi，但不是乱序RNAi，显著抑制蝰蛇蛋白表达，并且还显著逆转pIC诱导的HIV-1复制抑制。我们的结论是蝰蛇蛋白有助于诱导的TLR 3连接在星形胶质细胞的抗病毒状态，支持星形胶质细胞的作用，作为对感染的先天免疫反应的一部分，在中枢神经系统。
TLR3 functions as a viral nucleic acid sentinel activated by dsRNA viruses and virus replication intermediates within intracellular vesicles. To explore the spectrum of genes induced in human astrocytes by TLR3, we used a microarray approach and the analog polyriboinosinic polyribocytidylic acid (pIC) as ligand. As expected for TLR activation, pIC induced a wide array of cytokines and chemokines known for their role in inflammatory responses, as well as up-regulation of the receptor itself. The data also showed activation of a broad spectrum of antiviral response genes. To determine whether pIC induced an antiviral state in astrocytes, a pseudotyped HIV viral particle, vesicular stomatitis virus g-env-HIV-1, was used. pIC significantly abrogated HIV-1 replication, whereas IL-1, which also potently activates astrocytes, did not. One of the most highly up-regulated genes on microarray was the protein viperin/cig5. We found that viperin/cig5 expression was dependent on IFN regulatory factor 3 and NF-kappa B signaling, and that repetitive stimulation with pIC, but not IL-1, further increased expression. Viperin induction could also be substantially inhibited by neutralizing Abs to IFN-beta, as could HIV-1 replication. To explore a role for viperin in IFN-beta-mediated inhibition of HIV-1, we used an RNA interference (RNAi) approach. RNAi directed against viperin, but not a scrambled RNAi, significantly inhibited viperin expression, and also significantly reversed pIC-induced inhibition of HIV-1 replication. We conclude that viperin contributes to the antiviral state induced by TLR3 ligation in astrocytes, supporting a role for astrocytes as part of the innate immune response against infection in the CNS.