Melén K, Keskinen P, Lehtonen A, Julkunen I
Department of Virology, National Public Health Institute, Helsinki, Finland.
J Hepatol. 2000 Nov;33(5):764-72. doi: 10.1016/s0168-8278(00)80308-6.
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.
The results indicate positive feedback mechanisms in the IFN signaling system in hepatoma cells.
背景/目的：单独使用干扰素（IFN）-α或与其他抗病毒物质联合使用已被广泛用于治疗肝脏病毒感染。由于IFN在肝细胞中的作用分子机制相对不太清楚，我们研究了IFN诱导的人肝癌细胞系HepG2和HuH7中的基因表达和信号传导。
方法/结果：IFN与其特异性细胞表面受体结合导致Janus家族酪氨酸激酶（JAK）-信号转导子和转录激活子（STAT）途径的激活。我们观察到在HepG2和HuH7细胞中，IFN诱导的基因被IFN上调，但需要相对高浓度的IFN-α才能开启Mx A（一种抗病毒基因）和Mx B基因的表达。IFN-α受体（IFNAR1和IF-NAR2）、JAK1和TYK2 mRNA的基础表达很容易检测到，用IFN-α或IFN-γ处理后它们의表达没有明显改变。肝癌细胞中IFN信号分子STAT1、STAT2和p48的基础表达水平相对较低，但两种类型的IFN均强烈上调它们的表达。用低剂量的IFN-γ预处理HepG2或HuH7，然后用IFN-α刺激，导致IFN-α特异性信号复合物ISGF3的形成显著增强。
结果表明肝癌细胞中IFN信号系统存在正反馈机制。
