title: Herpes simplex virus type 2 induces secretion of IL-12 by macrophages through a mechanism involving NF-kappaB.
abstract: Interleukin (IL)-12 is an important proinflammatory and immunoregulatory cytokine expressed primarily by macrophages. Although IL-12 appears to be essential for clearance of many bacterial and parasitic infections, only little is known about the production and regulation of this cytokine during viral infections. In this study we have shown that infection of mouse macrophages with herpes simplex virus type 2 (HSV-2) induces secretion of the p40 subunit of IL-12, and this induction was synergistically enhanced by interferon (IFN)-gamma. The production of IL-12 p40 was accompanied by production of bioactive IL-12 p70, since HSV-2-induced IFN-gamma secretion was blocked by neutralizing antibodies against IL-12. The IL-12-inducing effect of HSV-2 was abrogated when virus infectivity was destroyed by heat or UV irradiation, indicating that a functional viral genome is required and that interaction of viral glycoproteins with cellular receptors is not sufficient. Production of IL-12 p40 was transcriptionally regulated and required de novo protein synthesis. Although IFN-alpha, IL-1beta and tumour necrosis factor-alpha marginally influenced IL-12 production, they did not seem to constitute the endogenous factor(s) responsible for the effect of the virus infection. HSV-2 infection induced nuclear-binding activity to the kappaB halfsite of the IL-12 p40 promoter, and inhibitors of nuclear factor (NF)-kappaB activation significantly reduced IL-12 p40 production in infected cells. Collectively our data show that HSV-2 infection of murine macrophages induces production of IL-12 through a mechanism requiring intermediary synthesis of viral or host proteins and involving activation of NF-kappaB.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Aarhus, The Bartholin Building, DK-8000 Aarhus C, Denmark1.
authors.forename: Lene
authors.initials: L
authors.lastname: Malmgaard
authors.affiliation: Department of Medical Microbiology and Immunology, University of Aarhus, The Bartholin Building, DK-8000 Aarhus C, Denmark1.
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
authors.affiliation: Department of Medical Microbiology and Immunology, University of Aarhus, The Bartholin Building, DK-8000 Aarhus C, Denmark1.
authors.forename: Søren C
authors.initials: SC
authors.lastname: Mogensen
authors.affiliation: Department of Medical Microbiology and Immunology, University of Aarhus, The Bartholin Building, DK-8000 Aarhus C, Denmark1.
authors.forename: Svend
authors.initials: S
authors.lastname: Ellermann-Eriksen
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics / Q000378:metabolism; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000502:physiology*; D016898:Interferon-alpha / Q000494:pharmacology / Q000502:physiology; D016899:Interferon-beta / Q000494:pharmacology / Q000502:physiology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000821:virology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009500:Neutralization Tests; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects
chemical_list: D016898:Interferon-alpha; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D018664:Interleukin-12; D016899:Interferon-beta; D007371:Interferon-gamma; D004247:DNA