title: MAP kinase p38α regulates type III interferon (IFN-λ1) gene expression in human monocyte-derived dendritic cells in response to RNA stimulation.
abstract: Recognition of viral nucleic acids leads to type I and type III IFN gene expression and activation of host antiviral responses. At present, type III IFN genes are the least well-characterized IFN types. Here, we demonstrate that the p38 MAPK signaling pathway is involved in regulating IFN-λ1 gene expression in response to various types of RNA molecules in human moDCs. Inhibition of p38 MAPK strongly reduced IFN gene expression, and overexpression of p38α MAPK enhanced IFN-λ1 gene expression in RNA-stimulated moDCs. The regulation of IFN gene expression by p38 MAPK signaling was independent of protein synthesis and thus, a direct result of RNA stimulation. Moreover, the RIG-I/MDA5-MAVS-IRF3 pathway was required for p38α MAPK to up-regulate IFN-λ1 promoter activation, whereas the MyD88-IRF7 pathway was not needed, and the regulation was not involved directly in IRF7-dependent IFN-α1 gene expression. The stimulatory effect of p38α MAPK on IFN-λ1 mRNA expression in human moDCs did not take place directly via the activating TBK1/IKKε complex, but rather, it occurred through some other parallel pathways. Furthermore, mutations in ISRE and NF-κB binding sites in the promoter region of the IFN-λ1 gene led to a significant reduction in p38α MAPK-mediated IFN responses after RNA stimulation. Altogether, our data suggest that the p38α MAPK pathway is linked with RLR signaling pathways and regulates the expression of early IFN genes after RNA stimulation cooperatively with IRF3 and NF-κB to induce antiviral responses further.
authors.affiliation: *Virology Unit, Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki, Finland; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA; Institute of Biotechnology and Department of Biosciences, University of Helsinki, Finland; and Department of Virology, University of Turku, Finland miao.jiang@helsinki.fi miao.jiang@thl.fi ilkka.julkunen@thl.fi ilkka.julkunen@utu.fi.
authors.forename: Miao
authors.initials: M
authors.lastname: Jiang
authors.affiliation: *Virology Unit, Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki, Finland; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA; Institute of Biotechnology and Department of Biosciences, University of Helsinki, Finland; and Department of Virology, University of Turku, Finland.
authors.forename: Pamela
authors.initials: P
authors.lastname: Österlund
authors.affiliation: *Virology Unit, Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki, Finland; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA; Institute of Biotechnology and Department of Biosciences, University of Helsinki, Finland; and Department of Virology, University of Turku, Finland.
authors.forename: Riku
authors.initials: R
authors.lastname: Fagerlund
authors.affiliation: *Virology Unit, Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki, Finland; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA; Institute of Biotechnology and Department of Biosciences, University of Helsinki, Finland; and Department of Virology, University of Turku, Finland.
authors.forename: Diana N
authors.initials: DN
authors.lastname: Rios
authors.affiliation: *Virology Unit, Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki, Finland; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA; Institute of Biotechnology and Department of Biosciences, University of Helsinki, Finland; and Department of Virology, University of Turku, Finland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: *Virology Unit, Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki, Finland; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA; Institute of Biotechnology and Department of Biosciences, University of Helsinki, Finland; and Department of Virology, University of Turku, Finland.
authors.forename: Minna M
authors.initials: MM
authors.lastname: Poranen
authors.affiliation: *Virology Unit, Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki, Finland; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA; Institute of Biotechnology and Department of Biosciences, University of Helsinki, Finland; and Department of Virology, University of Turku, Finland.
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Bamford
authors.affiliation: *Virology Unit, Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki, Finland; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA; Institute of Biotechnology and Department of Biosciences, University of Helsinki, Finland; and Department of Virology, University of Turku, Finland miao.jiang@helsinki.fi miao.jiang@thl.fi ilkka.julkunen@thl.fi ilkka.julkunen@utu.fi.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Julkunen
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology; D000072640:Interferon-Induced Helicase, IFIH1; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D012313:RNA / Q000494:pharmacology*; D011971:Receptors, Immunologic; D020218:Response Elements / Q000276:immunology; D000095022:Interferon Lambda
chemical_list: D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D000072640:Interferon-Induced Helicase, IFIH1; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D048308:Mitogen-Activated Protein Kinase 14; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D012313:RNA; D011971:Receptors, Immunologic; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494232:IRF3 protein, human; C494234:IRF7 protein, human; C554329:Ifna1 protein, mouse; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; C403191:TBK1 protein, human; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse; C452815:IFIH1 protein, human
keywords: IRF3; NF-κB; RIG-I-like receptors; signaling; transcription