title: Induction of cytokine expression by herpes simplex virus in human monocyte-derived macrophages and dendritic cells is dependent on virus replication and is counteracted by ICP27 targeting NF-kappaB and IRF-3.
abstract: Macrophages and dendritic cells (DCs) play essential roles in host defence against microbial infections. In the present study, it is shown that human monocyte-derived macrophages and DCs express both type I and type III interferons (IFNs) [IFN-alpha, IFN-beta and interleukin 28 (IL-28), IL-29, respectively], tumour necrosis factor alpha and the chemokines CCL5 and CXCL10 after herpes simplex virus 1 (HSV-1) infection. The cytokine-inducing activity of HSV-1 was dependent on viability of the virus, because UV-inactivated virus did not induce a cytokine response. Pretreatment of the cells with IFN-alpha or IL-29 strongly enhanced the HSV-1-induced cytokine response. Both IFN-alpha and IL-29 decreased viral immediate-early (IE) gene infected-cell protein 27 (ICP27) transcription, suggesting that IL-29 possesses antiviral activity against HSV-1 comparable to that of IFN-alpha. Macrophage infection with HSV-1 lacking functional ICP27 (d27-1 virus) resulted in strongly enhanced cytokine mRNA expression and protein production. In contrast, viruses lacking functional IE genes ICP0 and ICP4 induced cytokine responses comparable to those of the wild-type viruses. The activation of transcription factors IRF-3 and NF-kappaB was strongly augmented when macrophages were infected with the ICP27 mutant virus. Altogether, the results demonstrate that HSV-1 both induces and inhibits the antiviral response in human cells and that the type III IFN IL-29, together with IFN-alpha, amplifies the antiviral response against the virus. It is further identified that viral IE-gene expression interferes with the antiviral response in human macrophages and ICP27 is identified as an important viral protein counteracting the early innate immune response.
authors.affiliation: Institute of Medical Microbiology and Immunology, University of Aarhus, DK-8000 Aarhus C, Denmark.|Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland.
authors.forename: Jesper
authors.initials: J
authors.lastname: Melchjorsen
authors.affiliation: Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Sirén
authors.affiliation: Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Julkunen
authors.affiliation: Institute of Medical Microbiology and Immunology, University of Aarhus, DK-8000 Aarhus C, Denmark.
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
authors.affiliation: Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland.
authors.forename: Sampsa
authors.initials: S
authors.lastname: Matikainen
mesh_terms: D016207:Cytokines / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D005786:Gene Expression Regulation; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D016898:Interferon-alpha / Q000494:pharmacology; D007372:Interferons; D007378:Interleukins / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D014762:Viral Interference; D014779:Virus Replication; D000095022:Interferon Lambda
chemical_list: D016207:Cytokines; D017874:Immediate-Early Proteins; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D016328:NF-kappa B; D015534:Trans-Activators; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C057120:ICP27 protein, human herpesvirus 1; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C048925:herpes simplex virus, type 1 protein ICP4; C051804:Vmw110 protein, Human herpesvirus 1