Abstract
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+dim 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+dim 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.
Highlights
Hepatitis C virus (HCV) is a 9.6-kb hepatotropic RNA virus that is known to be a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma
To investigate whether neutralization of IL-10 has any effect on the surface expression of CD56 in Natural killer (NK)-92 cells, NK-92 cells were incubated in the presence or absence of anti-IL-10 (1 ng/mL) for 6 h and stained with fluorescent anti-CD56 antibodies
There was a significant increase in the frequency of the CD56+dim population of NK-92 cells (62.1%) in the presence of anti-IL-10 compared with untreated cells (41.7%) (Figure 1A,B)
Summary
Hepatitis C virus (HCV) is a 9.6-kb hepatotropic RNA virus that is known to be a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. With regard to innate immune responses, establishment of chronic HCV infection was shown to be partly related with NK cell dysfunction, which results in the modulation of DC function or the production of immunoregulatory cytokines (TGF-β, IL-10) during HCV infection [8,9]. Increased natural cytotoxicity receptor (NCR) expression of NK cells with IL-10 production was shown to provide a greater contribution to NK-DC crosstalk for subsequent adaptive immune responses than virus control in HCV infection [17]. We tried to induce the functional activation of NK cells by neutralizing IL-10 or adding exogenous IL-21 in coculture with J6/JFH1-huh 7.5 cells (HCVcc) and investigated the effect of cytokine-modulated natural killer cells on the activity of HCV. We explored the signaling molecules that are related with NK cell activation in coculture with J6/JFH1-huh 7.5 cells
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