Effect of interferon-λ1 on the secretion of IP-10 by hepatitis C virus-infected cells and the migration of natural killer cells

Abstract

Abstract Hepatitis C virus (HCV) is an important human pathogen because it causes chronic hepatitis, liver cirrhosis, and hepatoma. Interferon (IFN)-λ1, which inhibits viral replication, and natural killer (NK) cells, which kill virus-infected cells, would be important in the innate immunity to HCV infection. Although it cannot directly stimulate NK cells because of the absence of its receptors on NK cells, IFN-λ1 is able to bind the receptors on HCV-infected hepatocytes. This study investigated, therefore, whether the stimulation of HCV-infected hepatocytes by IFN-λ1 treatment modulated NK cell function. Cell-culture-generated HCV virions, hepatoma cell lines, such as Huh7.5 and HCV-core replicon Huh7 cells, and primary human NK cells were employed. IFN-λ1 responses and NK cell function were measured by qPCR, ELISA, western blot, migration assay, and flow cytometry. IFN-λ1 effectively reduced HCV replication and increased the expression of interferon-stimulated genes (ISGs), such as MX1 and IFIT1, in HCV-infected cells and replicon cells. In addition, IFN-λ1 enhanced the transcription of chemokines such as IP-10 and IL-8. In particular, IP-10 secretion by HCV-infected Huh7.5 cells and HCV-core replicon Huh7 cells was significantly increased after IFN-λ1 treatment. Although the concentration of IP-10 secreted by HCV-infected Huh7.5 cells in vitro was insufficient to elicit considerable migration of NK cells, recombinant IP-10 could induce migration of NK cells ex vivo. In conclusion, IFN-λ1 enhanced IP-10 secretion by HCV-infected cells and IP-10 could modulate NK cell migration. These results suggested that IFN-λ1 would indirectly regulate the chemotaxis of NK cells through augmenting IP-10 secretion by HCV-infected cells.