Cytokine-Modulated Natural Killer Cells Differentially Regulate the Activity of the Hepatitis C Virus

• Published in: International journal of molecular sciences 2018-09, Vol.19 (9), p.2771
• Main Authors: Cho, Yoo Jin, Lee, Hwan Hee, Kang, Hyojeung, Cho, Hyosun
• Format: Article
• Language: English
• Subjects: Activation; CD56 antigen; CD56 Antigen - metabolism; Cell culture; Cell Line; Core protein; Cytokines; Cytotoxicity; Extracellular Signal-Regulated MAP Kinases; Gene expression; Genotypes; HCV; Hepacivirus - immunology; Hepatitis; Hepatitis C; Hepatitis C - immunology; Hepatitis C - virology; Hepatocellular carcinoma; Host-Pathogen Interactions - immunology; huh 7.5; Humans; Immunology; Immunomodulation; Infections; Interferon-gamma - metabolism; Interleukin 10; Interleukin 21; Interleukin-10 - antagonists & inhibitors; Interleukin-10 - metabolism; Killer Cells, Lymphokine-Activated - immunology; Killer Cells, Lymphokine-Activated - metabolism; Kinases; Lymphocytes; Lymphoid cells; Macrophages; Natural killer cells; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacy; Proteins; STAT Transcription Factors - metabolism; Stat1 protein; Stat5 protein; Viral infections
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19092771

HCV genotype 2a strain JFH-1 replicates and produces viral particles efficiently in human hepatocellular carcinoma (huh) 7.5 cells, which provide a stable in vitro cell infection system for the hepatitis C virus (HCVcc system). Natural killer (NK) cells are large lymphoid cells that recognize and kill virus-infected cells. In this study, we investigated the interaction between NK cells and the HCVcc system. IL-10 is a typical immune regulatory cytokine that is produced mostly by NK cells and macrophages. IL-21 is one of the main cytokines that stimulate the activation of NK cells. First, we used anti-IL-10 to neutralize IL-10 in a coculture of NK cells and HCVcc. Anti-IL-10 treatment increased the maturation of NK cells by enhancing the frequency of the CD56 population in NK-92 cells. However, with anti-IL-10 treatment of NK cells in coculture with J6/JFH-1-huh 7.5 cells, there was a significant decrease in the expression of STAT1 and STAT5 proteins in NK-92 cells and an increase in the HCV Core and NS3 proteins. In addition, rIL-21 treatment increased the frequency of the CD56 population in NK-92 cells, Also, there was a dramatic increase in the expression of STAT1 and STAT5 proteins in rIL-21 pre-stimulated NK cells and a decrease in the expression of HCV Core protein in coculture with J6/JFH-1-huh 7.5 cells. In summary, we found that the functional activation of NK cells can be modulated by anti-IL-10 or rIL-21, which controls the expression of HCV proteins as well as HCV RNA replication.