title: Influenza A and sendai viruses induce differential chemokine gene expression and transcription factor activation in human macrophages.
abstract: 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.
authors.affiliation: Department of Virology, National Public Health Institute, Helsinki, FIN-00300, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Matikainen
authors.forename: J
authors.initials: J
authors.lastname: Pirhonen
authors.forename: M
authors.initials: M
authors.lastname: Miettinen
authors.forename: A
authors.initials: A
authors.lastname: Lehtonen
authors.forename: C
authors.initials: C
authors.lastname: Govenius-Vintola
authors.forename: T
authors.initials: T
authors.lastname: Sareneva
authors.forename: I
authors.initials: I
authors.lastname: Julkunen
mesh_terms: D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics*; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D050856:Interferon Regulatory Factor-1; D007372:Interferons / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D010750:Phosphoproteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018108:Respirovirus / Q000502:physiology*; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D018925:Chemokines; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D004247:DNA; D007372:Interferons; D003513:Cycloheximide