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 in flammation. Here we show that influenza A- or Sendai virus-infected human m acrophages produce MIP-1 alpha, MIP-1 beta, RANTES, MCP-1, MCP-3, MIP-3 alp ha, IP-10, and IL-8, whereas no upregulation of MIP-3 beta, eotaxin, or MDC production was detected. Influenza A virus was a better inducer of MCP-1 a nd MCP-3 production than Sendai virus, whereas MIP-1 alpha, MIP-1 beta, RAN TES, MIP-3 alpha, and IL-8 were induced preferentially by Sendai virus. Inf ection in the presence of protein synthesis inhibitor indicated that ongoin g protein synthesis was required for influenza A virus-induced expression o f MCP-1, MCP-3, and IP-10 genes, whereas Sendai virus-induced chemokine mRN A expression took place in the absence of de novo protein synthesis. Neutra lization of virus-induced IFN-alpha/beta resulted in downregulation or viru s-induced IP-10, MCP-1, and MCP-3 mRNA expression. IFN-alpha or IFN-gamma w ere 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 diffe rentially activated by these viruses. Influenza A virus more efficiently ac tivated ISGF3 complex formation and Stat1 DNA-binding compared to Sendai vi rus, which in turn was a more potent activator of IRF-1. Our results show t hat during viral infections macrophages predominantly produce monocyte and Th1 cell attracting chemokines. Furthermore, virus-induced IFN-alpha/beta e nhanced chemokine gene expression in macrophages emphasizing the role or IF N-alpha/beta in the development of Th1 immune responses. (C) 2000 Academic Press.