Interferon-induced gene expression and signaling in human hepatoma cell lines.
OBJECTIVE
Interferon(IFN)-alpha alone or combined with other antiviral substances has been extensively used for the treatment of viral infections of the liver. Since the molecular mechanisms of IFN action in liver cells are relatively poorly characterized, we studied IFN-induced gene expression and signaling in human hepatoma, HepG2 and HuH7 cell lines.


RESULTS
IFN binding to its specific cell surface receptor leads to activation of the Janus family tyrosine kinase (JAK) - signal transducer and activator of transcription (STAT) pathway. We observed that in HepG2 and HuH7 cells IFN-inducible genes were upregulated by IFNs, but relatively high concentrations of IFN-alpha were needed to turn on MxA (an antiviral gene) and MxB gene expression. The basal expression of IFN-alpha receptor (IFNAR1 and IF-NAR2) JAK1 and TYK2 mRNAs was readily detectable, and their expression was not significantly altered by treatment with either IFN-alpha or IFN-gamma. Hepatoma cells possessed relatively low basal expression levels of IFN signaling molecules STAT1, STAT2 and p48, but their expression was strongly upregulated by both types of IFNs. Pretreatment of HepG2 or HuH7 with low IFN-gamma doses, followed by stimulation with IFN-alpha, resulted in a marked enhancement of the formation of IFN-alpha-specific signaling complex ISGF3.


CONCLUSIONS
The results indicate positive feedback mechanisms in the IFN signaling system in hepatoma cells.
Melén
K
K
Department of Virology, National Public Health Institute, Helsinki, Finland. krister.melen@ktl.fi
Keskinen
P
P
Lehtonen
A
A
Julkunen
I
I
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D053613:Janus Kinase 1; D008099:Liver / Q000378:metabolism*; D064547:Myxovirus Resistance Proteins; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000235:genetics; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D015534:Trans-Activators / Q000235:genetics; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; C579071:MX1 protein, human; C579068:MX2 protein, human; D064547:Myxovirus Resistance Proteins; D011506:Proteins; D012333:RNA, Messenger; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D015534:Trans-Activators; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D019204:GTP-Binding Proteins