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Monocytes activate natural killer cells via inflammasome-induced interleukin 18 in response to hepatitis C virus replication.
- Source :
-
Gastroenterology [Gastroenterology] 2014 Jul; Vol. 147 (1), pp. 209-220.e3. Date of Electronic Publication: 2014 Mar 28. - Publication Year :
- 2014
-
Abstract
- 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.<br />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.<br />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.<br />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.<br /> (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Cell Communication physiology
Cell Line, Tumor
Coculture Techniques
Hepatitis C, Chronic pathology
Hepatitis C, Chronic physiopathology
Hepatocytes pathology
Hepatocytes physiology
Hepatocytes virology
Humans
Interferon-gamma physiology
Killer Cells, Natural pathology
Liver Neoplasms pathology
Liver Neoplasms physiopathology
Monocytes pathology
Hepacivirus physiology
Inflammasomes physiology
Interleukin-18 physiology
Killer Cells, Natural physiology
Monocytes physiology
Virus Replication physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 147
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 24685721
- Full Text :
- https://doi.org/10.1053/j.gastro.2014.03.046