Monocytes activate natural killer cells via inflammasome-induced interleukin 18 in response to hepatitis C virus replication.
BACKGROUND & AIMS
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.
['Serti|Elisavet|E|', 'Werner|Jens M|JM|', 'Chattergoon|Michael|M|', 'Cox|Andrea L|AL|', 'Lohmann|Volker|V|', 'Rehermann|Barbara|B|']
D002450:Cell Communication D045744:Cell Line, Tumor D018920:Coculture Techniques D016174:Hepacivirus D019698:Hepatitis C, Chronic D022781:Hepatocytes D006801:Humans D058847:Inflammasomes D007371:Interferon-gamma D020382:Interleukin-18 D007694:Killer Cells, Natural D008113:Liver Neoplasms D009000:Monocytes D014779:Virus Replication
Cytokine Production Hepatocyte Immune Response Viral Replication