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High-throughput Quantitative Real-time RT-PCR Assay for Determining Expression Profiles of Types I and III Interferon Subtypes
Published on: March 24, 2015
Interferon-induced gene expression and signaling in human hepatoma cell lines
K Melén1, P Keskinen, A Lehtonen
1Department of Virology, National Public Health Institute, Helsinki, Finland. krister.melen@ktl.fi
Background/Aim:
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.
Methods/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.
Conclusion:
The results indicate positive feedback mechanisms in the IFN signaling system in hepatoma cells.
Insights
Interferon (IFN) signaling in liver cancer cells shows positive feedback. While IFNs upregulate antiviral genes, specific pathways require higher concentrations for activation, suggesting complex regulatory mechanisms in hepatoma cells.
Area of Science:
- Hepatology
- Molecular Biology
- Immunology
Background:
- Interferon (IFN)-alpha is used to treat liver viral infections.
- Molecular mechanisms of IFN action in liver cells are not fully understood.
Purpose of the Study:
- Investigate IFN-induced gene expression and signaling pathways in human hepatoma cell lines (HepG2 and HuH7).
Main Methods:
- Studied IFN-induced gene expression and signaling in HepG2 and HuH7 cells.
- Analyzed the Janus kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathway.
- Examined the expression of IFN receptors, JAKs, STATs, and IFN-inducible genes (MxA, MxB).
Main Results:
- IFN-inducible genes were upregulated, but MxA and MxB required high IFN-alpha concentrations.
- Basal expression of IFNAR1, IFNAR2, JAK1, and TYK2 was detectable and unaffected by IFNs.
- Hepatoma cells had low basal STAT1, STAT2, and p48, but these were strongly upregulated by IFNs.
- IFN-gamma pretreatment enhanced IFN-alpha-induced ISGF3 complex formation.
Conclusions:
- Hepatoma cells exhibit positive feedback mechanisms within the IFN signaling system.
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