Influenza A and sendai viruses induce differential chemokine gene expression and transcription factor activation in human macrophages.

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.