Matikainen S, Pirhonen J, Miettinen M, Lehtonen A, Govenius-Vintola C, Sareneva T, Julkunen I
Department of Virology, National Public Health Institute, Helsinki, FIN-00300, Finland.
Virology. 2000 Oct 10;276(1):138-47. doi: 10.1006/viro.2000.0542.
Chemokines regulate leukocyte traffic and extravasation into the site of inflammation. Here we show that influenza A- or Sendai virus-infected human macrophages produce MIP-1alpha, MIP-1beta, RANTES, MCP-1, MCP-3, MIP-3alpha, IP-10, and IL-8, whereas no upregulation of MIP-3beta, eotaxin, or MDC production was detected. Influenza A virus was a better inducer of MCP-1 and MCP-3 production than Sendai virus, whereas MIP-1alpha, MIP-1beta, RANTES, MIP-3alpha, and IL-8 were induced preferentially by Sendai virus. Infection in the presence of protein synthesis inhibitor indicated that ongoing protein synthesis was required for influenza A virus-induced expression of MCP-1, MCP-3, and IP-10 genes, whereas Sendai virus-induced chemokine mRNA expression took place in the absence of de novo protein synthesis. Neutralization of virus-induced IFN-alpha/beta resulted in downregulation of virus-induced IP-10, MCP-1, and MCP-3 mRNA expression. IFN-alpha or IFN-gamma were found to directly enhance MCP-1, MCP-3, and IP-10 mRNA expression. Both influenza A and Sendai viruses similarly activated transcription factor NF-kappaB. In contrast to NF-kappaB, IRFs and STATs, the other transcription factors involved in the regulation of chemokine gene expression, were differentially activated by these viruses. Influenza A virus more efficiently activated ISGF3 complex formation and Stat1 DNA-binding compared to Sendai virus, which in turn was a more potent activator of IRF-1. Our results show that during viral infections macrophages predominantly produce monocyte and Th1 cell attracting chemokines. Furthermore, virus-induced IFN-alpha/beta enhanced chemokine gene expression in macrophages emphasizing the role of IFN-alpha/beta in the development of Th1 immune responses.
趋化因子调节白细胞的迁移以及向炎症部位的渗出。在此我们发现，甲型流感病毒或仙台病毒感染的人类巨噬细胞会产生MIP-1α、MIP-1β、RANTES、MCP-1、MCP-3、MIP-3α、IP-10和IL-8，而未检测到MIP-3β、嗜酸性粒细胞趋化因子或MDC产生的上调。甲型流感病毒比仙台病毒更能诱导MCP-1和MCP-3的产生，而仙台病毒则优先诱导MIP-1α、MIP-1β、RANTES、MIP-3α和IL-8。在存在蛋白质合成抑制剂的情况下进行感染表明，甲型流感病毒诱导的MCP-1、MCP-3和IP-10基因表达需要持续的蛋白质合成，而仙台病毒诱导的趋化因子mRNA表达在没有从头合成蛋白质的情况下也能发生。对病毒诱导的IFN-α/β进行中和会导致病毒诱导的IP-10、MCP-1和MCP-3 mRNA表达下调。发现IFN-α或IFN-γ可直接增强MCP-1、MCP-3和IP-10 mRNA的表达。甲型流感病毒和仙台病毒同样能激活转录因子NF-κB。与NF-κB、IRF和STAT不同，参与趋化因子基因表达调控的其他转录因子被这些病毒差异性地激活。与仙台病毒相比，甲型流感病毒更有效地激活ISGF3复合物的形成和Stat1与DNA的结合，而仙台病毒反过来是IRF-1更有效的激活剂。我们的结果表明，在病毒感染期间，巨噬细胞主要产生吸引单核细胞和Th1细胞的趋化因子。此外，病毒诱导的IFN-α/β增强了巨噬细胞中趋化因子基因的表达，强调了IFN-α/β在Th1免疫反应发展中的作用。
