Endogenous levels of mRNA for IFNs and IFN-related genes in hepatic biopsies of chronic HCV-infected and non-alcoholic steatohepatitis patients

J Med Virol. 2003 Aug;70(4):581-7. doi: 10.1002/jmv.10433.

Abstract

To investigate the intra-hepatic activation of the IFN system in patients affected by chronic HCV-infection in comparison with that observed in a non-infectious liver disease such as non-alcoholic steatohepatitis, we measured the liver steady state mRNA levels of interferon-alpha, interferon-beta and interferon-gamma as well as of IFN-related genes (IFNAR-1, STAT1alpha, PKR, 2-5 AS, IRF-1, ICE and IL-18). In HCV-infected subjects, possible correlations of these parameters with viral load and liver injury were also analyzed. Twenty-four chronic untreated HCV-infected subjects and seven patients with non-alcoholic steatohepatitis were enrolled in the study. Liver biopsies were graded according to Knodell scores. Intra-hepatic mRNA levels of IFNs and related genes were assessed by semi-quantitative RT-PCR. In comparison with non-alcoholic steatohepatitis, in HCV-infected subjects IFN-alpha and -beta mRNA levels were significantly lower, whereas IFN-gamma, IFNAR-1, STAT1alpha IRF-1, and IL-18 mRNA were upregulated. Moreover, IFN-gamma mRNA steady state levels were correlated positively with those of IFNAR-1, IRF-1, and IL-18, suggesting a coordinated induction of these genes. Although plasma viral load was correlated inversely with IL-18-specific mRNA, viral load was not related to liver injury. IFN-gamma and IRF-1 mRNA levels were correlated positively with ALT, but not with the grading or staging. Conversely, IFN-alpha and -beta mRNA levels were higher in livers with lower staging scores. These findings support the hypothesis that in chronic HCV infection there is an imbalance between an upregulated IFN-gamma system and a downregulated IFN-alpha and -beta system, probably due to a mixed effect exerted by HCV-specific and inflammatory non-specific factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biopsy
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Hepacivirus / physiology
  • Hepatitis C, Chronic / immunology*
  • Hepatitis C, Chronic / pathology
  • Hepatitis C, Chronic / virology
  • Humans
  • Interferon Regulatory Factor-1
  • Interferons / classification
  • Interferons / genetics
  • Interferons / metabolism*
  • Interleukin-18 / genetics
  • Interleukin-18 / metabolism
  • Liver / immunology*
  • Liver / metabolism
  • Liver / pathology
  • Liver Diseases / immunology*
  • Liver Diseases / pathology
  • Male
  • Membrane Proteins
  • Middle Aged
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Receptor, Interferon alpha-beta
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism
  • STAT1 Transcription Factor
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Virus Replication

Substances

  • DNA-Binding Proteins
  • IFNAR1 protein, human
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Interleukin-18
  • Membrane Proteins
  • Phosphoproteins
  • RNA, Messenger
  • Receptors, Interferon
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Receptor, Interferon alpha-beta
  • Interferons