title: Monocytes activate natural killer cells via inflammasome-induced interleukin 18 in response to hepatitis C virus replication.
abstract: OBJECTIVE
  Production of interferon (IFN)-γ by natural killer (NK) cells is attenuated during chronic infection with hepatitis C virus (HCV). We investigated whether this is due to intrinsic or extrinsic mechanisms of NK cells.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) were collected from patients with chronic HCV infection or uninfected blood donors (controls); NK cells and monocytes were isolated or eliminated. We cultured hepatoma cells that express luciferase-tagged subgenomic HCV replicons (Huh7/HCV replicon cells) or their HCV-negative counterparts (Huh7) with NK cells in the presence or absence of other populations of PBMCs. Antiviral activity, cytotoxicity, and cytokine production were assessed.
  
  
  RESULTS
  NK cells produced greater amounts of IFN-γ when PBMC were cocultured with Huh7/HCV replicon cells than with Huh7 cells; NK cells and PBMCs from controls suppressed HCV replication to a greater extent than those from patients with chronic HCV infection. This antiviral effect was predominantly mediated by tumor necrosis factor (TNF)-α and IFN-γ. The antiviral activity of NK cells and their production of IFN-γ were reduced when they were used in coculture alone (rather than with PBMC), or after depletion of CD14(+) monocytes, after knockdown of the inflammasome in monocytes, or after neutralization of interleukin-18, which is regulated by the inflammasome. These findings indicate a role for monocytes in NK cell activation. Compared with control monocytes, monocytes from patients with chronic HCV infection had reduced TNF-α-mediated (direct) and reduced NK cell-mediated (indirect) antiviral effects. Control monocytes increased the antiviral effects of NK cells from patients with chronic HCV infection and their production of IFN-γ.
  
  
  CONCLUSIONS
  Monocytes sense cells that contain replicating HCV and respond by producing interleukin-18 via the inflammasome and by activating NK cells. Patients with chronic HCV infection have reduced monocyte function, attenuating NK cell IFN-γ-mediated responses.
authors.affiliation: Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Elisavet
authors.initials: E
authors.lastname: Serti
authors.affiliation: Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Werner
authors.affiliation: Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: Chattergoon
authors.affiliation: Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Cox
authors.affiliation: Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Lohmann
authors.affiliation: Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. Electronic address: rehermann@nih.gov.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rehermann
mesh_terms: D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000473:pathology / Q000503:physiopathology; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology / Q000821:virology; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology; D020382:Interleukin-18 / Q000502:physiology*; D007694:Killer Cells, Natural / Q000473:pathology / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology; D009000:Monocytes / Q000473:pathology / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D058847:Inflammasomes; D020382:Interleukin-18; D007371:Interferon-gamma
keywords: Cytokine Production; Hepatocyte; Immune Response; Viral Replication