Interferon-alpha activates multiple STAT signals and down-regulates c-Met in primary human hepatocytes

Gastroenterology. 2002 Apr;122(4):1020-34. doi: 10.1053/gast.2002.32388.


Background & aims: Interferon (IFN)-alpha therapy is currently the primary choice for viral hepatitis and a promising treatment for hepatocellular carcinoma (HCC). Primary mouse and rat hepatocytes respond poorly to IFN-alpha stimulation. Thus, it is very important to examine the IFN-alpha signal pathway in primary human hepatocytes.

Methods: The IFN-alpha-activated signals and genes in primary human hepatocytes and hepatoma cells were examined by Western blotting and microarray analyses.

Results: Primary human hepatocytes respond very well to IFN-alpha stimulation as shown by activation of multiple signal transducer and activator of transcription factor (STAT) 1, 2, 3, 5, and multiple genes. The differential response to IFN-alpha stimulation in primary human and mouse hepatocytes may be caused by expression of predominant functional IFN-alpha receptor 2c (IFNAR2c) in primary human hepatocytes vs. expression of predominant inhibitory IFNAR2a in mouse hepatocytes. Microarray analyses of primary human hepatocytes show that IFN-alpha up-regulates about 44 genes by over 2-fold and down-regulates about 9 genes by 50%. The up-regulated genes include a variety of antiviral and tumor suppressors/proapoptotic genes. The down-regulated genes include c-myc and c-Met, the hepatocyte growth factor (HGF) receptor. Down-regulation of c-Met is caused by IFN-alpha suppression of the c-Met promoter through down-regulation of Sp1 binding and results in attenuation of HGF-induced signals and cell proliferation.

Conclusions: IFN-alpha directly targets human hepatocytes, followed by activation of multiple STATs and regulation of a wide variety of genes, which may contribute to the antiviral and antitumor activities of IFN-alpha in human liver.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Carcinoma, Hepatocellular
  • Cell Division / drug effects
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation / drug effects
  • Female
  • Gene Expression / drug effects
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Humans
  • Immunologic Factors / pharmacology*
  • Interferon-alpha / pharmacology*
  • Interferon-gamma / pharmacology
  • Liver Neoplasms
  • Male
  • Membrane Proteins
  • Milk Proteins*
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins c-met / genetics*
  • Proto-Oncogene Proteins c-met / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Interferon alpha-beta
  • Receptors, Interferon / genetics
  • STAT1 Transcription Factor
  • STAT2 Transcription Factor
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Signal Transduction / drug effects*
  • Solubility
  • Sp1 Transcription Factor / metabolism
  • Trans-Activators / metabolism*
  • Tumor Cells, Cultured
  • Up-Regulation / drug effects


  • Antiviral Agents
  • DNA-Binding Proteins
  • Immunologic Factors
  • Interferon-alpha
  • Membrane Proteins
  • Milk Proteins
  • Receptors, Interferon
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT2 Transcription Factor
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT5 Transcription Factor
  • Sp1 Transcription Factor
  • Stat1 protein, rat
  • Stat3 protein, rat
  • Trans-Activators
  • Receptor, Interferon alpha-beta
  • Interferon-gamma
  • Proto-Oncogene Proteins c-met