Hyper-activated IRF-1 and STAT1 contribute to enhanced interferon stimulated gene (ISG) expression by interferon alpha and gamma co-treatment in human hepatoma cells.
Previous reports suggest that type I and type II Interferon can co-operatively inhibit some virus replication, e.g. HCV, SARS-CoV, HSV-1. To find out the molecular mechanism underlying this phenomenon, we analyzed the transcription profile stimulated by IFN-alpha and IFN-gamma in Huh-7 cells and found that the transcription of a subset of IFN stimulated genes (ISGs) including BclG, XAF1, TRAIL and TAP1 was enhanced when IFN-alpha and gamma were both present. Promoter analysis of BclG revealed that IRF-1 and STAT1 were both required in this process. Enhanced IRF-1/DNA complex formation was observed in interferon co-treatment group by gel shift analysis. Furthermore, IRF-1 activation was found to be generally required in this cluster of ISGs. STAT1 tyrosine phosphorylation was elevated by IFN combination treatment, however, only the hyper-transactivation of GAS but not ISRE was observed. In conclusion, hyper-activation of IRF-1 and elevated STAT1 dimer formation may be two general switches which contribute to a much more robust antiviral symphony against virus replication when type I and type II IFNs are co-administered.
Zhang
Xiao-Nan
XN
Key Laboratory of Medical Molecular Virology, Institute of Microbiology and Biomedical Sciences, Shanghai Medical College, Fudan University, China.
Liu
Jiang-Xia
JX
Hu
Yun-Wen
YW
Chen
Hui
H
Yuan
Zheng-Hong
ZH
D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D019281:Dimerization; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection
C428448:BCL2L14 protein, human; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma