Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.
J Immunol. 2010 Mar 1;184(5):2369-76. doi: 10.4049/jimmunol.0902712. Epub 2010 Feb 3.
IFN-beta production is an inaugural event in the innate immune response to viral infections, with relatively small fold changes in IFN-beta expression resulting in the activation of important antiviral signaling cascades. In our rapid SIV/macaque model of HIV encephalitis, the virus enters the CNS within 4 d of infection, accompanied by a marked IFN-beta response that wanes as SIV replication is controlled. The centrality of IFN-beta to the innate antiviral response in the CNS combines with the potential inflammatory damage associated with long-term activation of this pathway to suggest that IFN-beta may be subject to regulatory fine-tuning in addition to well-established transcriptional and message stability mechanisms of regulation. In this paper, we present for the first time evidence that microRNAs (miRNAs), including miR-26a, -34a, -145, and let-7b, may directly regulate IFN-beta in human and macaque cells. In primary primate macrophages, the main cell type implicated in HIV and SIV infection in the CNS, specific miRNAs reduce, whereas miRNA inhibitors enhance, IFN-beta protein production. The potential biologic significance of this regulation is supported by evidence of an apparent negative feedback loop, with increased expression of three IFN-beta-regulating miRNAs by primate macrophages exposed to recombinant IFN-beta or stimulated to produce IFN-beta. Thus, miRNAs may contribute significantly to the regulation of IFN-beta in innate immune responses.
IFN-β 的产生是病毒感染先天免疫反应的初始事件，IFN-β 表达的相对较小变化会导致重要的抗病毒信号级联反应被激活。在我们的 SIV/猴 HIV 脑炎快速模型中，病毒在感染后 4 天内进入中枢神经系统，伴随着明显的 IFN-β 反应，随着 SIV 复制得到控制，这种反应逐渐减弱。IFN-β 在中枢神经系统中的先天抗病毒反应中的核心地位，加上与该途径的长期激活相关的潜在炎症损伤，表明 IFN-β 可能除了已建立的转录和消息稳定性调节机制外，还受到调节的精细调控。在本文中，我们首次提出证据表明，microRNAs（miRNAs），包括 miR-26a、-34a、-145 和 let-7b，可能直接调节人类和猕猴细胞中的 IFN-β。在原代灵长类巨噬细胞中，这是中枢神经系统中 HIV 和 SIV 感染所涉及的主要细胞类型，特定的 miRNAs 减少了 IFN-β 蛋白的产生，而 miRNA 抑制剂则增强了 IFN-β 蛋白的产生。这种调节的潜在生物学意义得到了支持，即暴露于重组 IFN-β 或被刺激产生 IFN-β 的灵长类巨噬细胞中，三种 IFN-β 调节 miRNA 的表达增加。因此，miRNAs 可能在先天免疫反应中 IFN-β 的调节中发挥重要作用。
