Regulation of IFN regulatory factor-7 and IFN-α production by enveloped virus and lipopolysaccharide in human plasmacytoid dendritic cells
Regulation of IFN regulatory factor-7 and IFN-α production by enveloped virus and lipopolysaccharide in human plasmacytoid dendritic cells
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DOI：
10.4049/jimmunol.173.3.1535
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发表时间：
2004-08-01
影响因子：
4.4
通讯作者：
Fitzgerald-Bocarsly, P
中科院分区：
文献类型：
--
作者：
Dai, JH;Megjugorac, NJ;Fitzgerald-Bocarsly, P
人浆细胞样树突状细胞（PDC）是暴露于包膜病毒和TLR-7和TLR-9配体后IFN-α的主要来源。虽然IFN调节因子-7（IRF-7）已知在IFN-α基因的病毒激活转录中起重要作用，但对人PDC中IFN-α产生的分子机制仍知之甚少。我们和其他人最近报道了与其他PBMC相比，PDC中IRF-7表达的组成性水平高。在这项研究中，我们证明，LPS和HSV上调IRF-7在PDC中的表达，并且这种IRF-7的增强依赖于NF-κ B的激活。NF-κ B抑制剂MG 132和吡咯烷二硫代氨基甲酸酯可有效抑制HSV或LPS诱导的IRF-7的表达，下调IRF-7在PDC中的组成型表达，阻断HSV诱导的IFN-α的产生。此外，我们发现IRF-7的核转位在对HSV刺激的反应中迅速发生，但在对LPS的反应中不发生，这与病毒而不是LPS刺激IFN-α产生一致。虽然LPS本身不能诱导IFN-α产生，但它导致PDC上TLR-4的快速上调，并增加了PDC中HSV诱导的IFN-α产生的幅度并加速了其动力学，提供了在混合感染情况下可能起作用的机制。与目前在细胞系中建立的IFN-α调节的概念相反，本研究强烈支持PDC中IRF-7表达的高组成性水平的立即可用性，并表明IRF-7所需的激活有助于病毒刺激的PDC中IFN-α的产生。
Human plasmacytoid dendritic cells (PDC) are a major source of IFN-alpha upon exposure to enveloped viruses and TLR-7 and TLR-9 ligands. Although IFN regulatory factor-7 (IRF-7) is known to play an essential role in virus-activated transcription of IFN-alpha genes, the molecular mechanisms of IFN-alpha production in human PDC remain poorly understood. We and others have recently reported high constitutive levels of IRF-7 expression in PDC as compared with other PBMC. In this study, we demonstrate that both LPS and HSV up-regulate the expression of IRF-7 in PDC, and that this enhancement of IRF-7 is dependent on NF-kappaB activation. The NF-kappaB inhibitors MG132 and pyrrolidinedithiocarbamate efficiently inhibited the induction of IRF-7 by HSV or LPS, and also down-regulated the constitutive expression of IRF-7 in PDC and blocked the HSV-induced production of IFN-alpha. In addition, we found that nuclear translocation of IRF-7 occurred rapidly in response to HSV stimulation, but not in response to LPS, which is consistent with the stimulation of IFN-alpha production by virus and not by LPS. Although LPS by itself was not able to induce IFN-alpha production, it led to rapid up-regulation of TLR-4 on PDC and increased the magnitude and accelerated the kinetics of HSV-induced IFN-alpha production in PDC, providing a mechanism that might be operative in a scenario of mixed infection. In contrast to the current concept of IFN-alpha regulation established in cell lines, this study strongly supports the immediate availability of high constitutive levels of IRF-7 expression in PDC, and suggests an activation required for IRF-7 that contributes to IFN-alpha production in virus-stimulated PDC.