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...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
28 March 2014
|
| In: |
Gastroenterology
Year: 2014, Volume: 147, Issue: 1, Pages: 209-220.e3 |
| ISSN: | 1528-0012 |
| DOI: | 10.1053/j.gastro.2014.03.046 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1053/j.gastro.2014.03.046 Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S0016508514004430 
|
| Author Notes: | Elisavet Serti, Jens M. Werner, Michael Chattergoon, Andrea L. Cox, Volker Lohmann, and Barbara Rehermann |
| Summary: | 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. |
|---|---|
| Item Description: | Gesehen am 21.08.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1528-0012 |
| DOI: | 10.1053/j.gastro.2014.03.046 |