title: Critical role of interferon-α constitutively produced in human hepatocytes in response to RNA virus infection.
abstract: Several viruses are known to infect human liver and cause the hepatitis, but the interferon (IFN) response, a first-line defense against viral infection, of virus-infected hepatocytes is not clearly defined yet. We investigated innate immune system against RNA viral infection in immortalized human hepatocytes (HuS-E/2 cells), as the cells showed similar early innate immune responses to primary human hepatocytes (PHH). The low-level constitutive expression of IFN-α1 gene, but not IFN-β and IFN-λ, was observed in both PHH and HuS-E/2 cells in the absence of viral infection, suggesting a particular subtype(s) of IFN-α is constitutively produced in human hepatocytes. To examine the functional role of such IFN-α in the antiviral response, the expression profiles of innate immune-related genes were studied in the cells with the treatment of neutralization against type I IFN receptor 2 (IFNAR2) or IFN-α itself to inhibit the constitutive IFN-α signaling before and after virus infection. As the results, a clear reduction of basal level expression of IFN-inducible genes was observed in uninfected cells. When the effect of the inhibition on the cells infected with hepatitis C virus (HCV) was examined, the significant decrease of IFN stimulated gene expression and the enhancement of initial HCV replication were observed, suggesting that the steady-state production of IFN-α plays a role in amplification of antiviral responses to control the spread of RNA viral infection in human hepatocytes.
authors.affiliation: Laboratory of Human Tumor Viruses, Institute for Virus Research, Kyoto University, Kyoto, Japan ; Laboratory of Viral Oncology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Tsugawa
authors.affiliation: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.affiliation: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Kunitada
authors.initials: K
authors.lastname: Shimotohno
authors.affiliation: Laboratory of Human Tumor Viruses, Institute for Virus Research, Kyoto University, Kyoto, Japan ; Laboratory of Viral Oncology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hijikata
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D019084:Fluorescent Antibody Technique, Indirect; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D015151:Immunoblotting; D016898:Interferon-alpha / Q000276:immunology*; D012327:RNA Virus Infections / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D057134:Antibodies, Neutralizing; D017931:DNA Primers; D016898:Interferon-alpha