title: Ribavirin regulates hepatitis C virus replication through enhancing interferon-stimulated genes and interleukin 8.
abstract: BACKGROUND
  The manner in which ribavirin (RBV) enhances the antiviral effects of interferon (IFN) against hepatitis C virus (HCV) remains unknown. We investigated whether RBV modifies IFN-stimulated genes (ISGs) in vivo and in vitro.
  
  
  METHODS
  We measured the messenger RNA (mRNA) levels of ISGs in T lymphocytes from patients with HCV infection who were receiving IFN-α therapy with or without RBV. We added RBV and/or IFN-α to a plasmid-based HCV replication system containing a full-length HCV genotype 1a sequence in HepG2 and Huh7 cell lines and the JFH-1 HCV genotype 2a sequence in Huh7 cell lines and measured levels of ISGs and autocrine IFN-β.
  
  
  RESULTS
  The expression of protein kinase R and myxovirus resistance A mRNA was enhanced more with IFN-α and RBV than by IFN-α alone in assays in vivo and in vitro. Such enhancement depended on autocrine IFN-β being enhanced by RBV. RBV upregulated interleukin 8 (IL-8) in the absence of IFN-α. The IL-8 upregulation induced by RBV was responsible for the activation of activator protein 1 (AP-1).
  
  
  CONCLUSIONS
  Ribavirin augments the anti-HCV effects of IFN-α induced by ISGs through enhancing autocrine IFN-β. Moreover, RBV can enhance IL-8 through activating AP-1. Improved understanding of ISG modulation by RBV would help to establish a means of eliminating HCV.
authors.affiliation: Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Tokumoto
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hiasa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Uesugi
authors.forename: Takao
authors.initials: T
authors.lastname: Watanabe
authors.forename: Toshie
authors.initials: T
authors.lastname: Mashiba
authors.forename: Masanori
authors.initials: M
authors.lastname: Abe
authors.forename: Teru
authors.initials: T
authors.lastname: Kumagi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Bunzo
authors.initials: B
authors.lastname: Matsuura
authors.forename: Morikazu
authors.initials: M
authors.lastname: Onji
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000187:drug effects* / Q000254:growth & development* / Q000276:immunology; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012254:Ribavirin / Q000008:administration & dosage / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology; D015533:Transcriptional Activation; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C508606:CXCL8 protein, human; D016898:Interferon-alpha; D016209:Interleukin-8; D012254:Ribavirin; D016899:Interferon-beta