期刊
GASTROENTEROLOGY
卷 147, 期 1, 页码 209-U343出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2014.03.046
关键词
Immune Response; Cytokine Production; Hepatocyte; Viral Replication
资金
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health intramural research program
- Deutsche Forschungsgemeinschaft (Bonn, Germany) [We-4675/1-1]
BACKGROUND & AIMS: Production of interferon (IFN)-gamma 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-gamma 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)-alpha and IFN-gamma. The antiviral activity of NK cells and their production of IFN-gamma 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-alpha-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-gamma. 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-gamma-mediated responses.
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