title: Dysregulation of interferon regulatory factors impairs the expression of immunostimulatory molecules in hepatitis C virus genotype 1-infected hepatocytes.
abstract: BACKGROUND
  IL-7 and IL-15 are produced by hepatocytes and are critical for the expansion and function of CD8 T cells. IL-15 needs to be presented by IL-15Rα for efficient stimulation of CD8 T cells.
  
  
  METHODS
  We analysed the hepatic levels of IL-7, IL-15, IL-15Rα and interferon regulatory factors (IRF) in patients with chronic hepatitis C (CHC) (78% genotype 1) and the role of IRF1 and IRF2 on IL-7 and IL-15Rα expression in Huh7 cells with or without hepatitis C virus (HCV) replicon.
  
  
  RESULTS
  Hepatic expression of both IL-7 and IL-15Rα, but not of IL-15, was reduced in CHC. These patients exhibited decreased hepatic IRF2 messenger RNA levels and diminished IRF2 staining in hepatocyte nuclei. We found that IRF2 controls basal expression of both IL-7 and IL-15Rα in Huh7 cells. IRF2, but not IRF1, is downregulated in cells with HCV genotype 1b replicon and this was accompanied by decreased expression of IL-7 and IL-15Rα, a defect reversed by overexpressing IRF2. Treating Huh7 cells with IFNα plus oncostatin M increased IL-7 and IL-15Rα mRNA more intensely than either cytokine alone. This effect was mediated by strong upregulation of IRF1 triggered by the combined treatment. Induction of IRF1, IL-7 and IL-15Rα by IFNα plus oncostatin M was dampened in replicon cells but the combination was more effective than either cytokine alone.
  
  
  CONCLUSIONS
  HCV genotype 1 infection downregulates IRF2 in hepatocytes attenuating hepatocellular expression of IL-7 and IL-15Rα. Our data reveal a new mechanism by which HCV abrogates specific T-cell responses and point to a novel therapeutic approach to stimulate anti-HCV immunity.
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), , Pamplona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Larrea
authors.forename: Jose-I
authors.initials: JI
authors.lastname: Riezu-Boj
authors.forename: Rafael
authors.initials: R
authors.lastname: Aldabe
authors.forename: Laura
authors.initials: L
authors.lastname: Guembe
authors.forename: Itziar
authors.initials: I
authors.lastname: Echeverria
authors.forename: Anangi
authors.initials: A
authors.lastname: Balasiddaiah
authors.forename: Pablo
authors.initials: P
authors.lastname: Gastaminza
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Civeira
authors.forename: Pablo
authors.initials: P
authors.lastname: Sarobe
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
mesh_terms: D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000235:genetics / Q000502:physiology; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology* / Q000821:virology; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis / Q000502:physiology; D050836:Interferon Regulatory Factor-2 / Q000096:biosynthesis / Q000502:physiology; D050835:Interferon Regulatory Factors / Q000502:physiology*; D019409:Interleukin-15 / Q000096:biosynthesis / Q000502:physiology; D053720:Interleukin-15 Receptor alpha Subunit / Q000096:biosynthesis / Q000502:physiology; D015851:Interleukin-7 / Q000096:biosynthesis / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D014779:Virus Replication / Q000502:physiology
chemical_list: C494257:IRF1 protein, human; C494229:IRF2 protein, human; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D050835:Interferon Regulatory Factors; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D015851:Interleukin-7
keywords: Chronic Viral Hepatitis; Gene Expression; HCV; Immune Response