| Full description or Abstract | Toggle abstract view 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. |
| Keywords & MeSH headings | Proto-Oncogene Protein c-met,Sp1/metabolism,Oligonucleotide Array Sequence Analysis,Down-Regulation/drug effects,Tumor Cells,Liver Neoplasms,Carcinoma,genetics,Cell Division/drug effects,Cultured,metabolism,Male,Transcription Factor,Solubility,Antiviral Agents/pharmacology,Gene Expression/drug effects,Interferon-alpha,Interferon/genetics,Hepatocytes,Female,pharmacology,Milk Proteins,Rats,Interferon Type II/pharmacology,DNA-Binding Proteins,Humans,Receptors,drug effects,Signal Transduction,Sprague-Dawley,cytology,Biological Response Modifiers,Up-Regulation/drug effects,Trans-Activators,Hepatocellular |