International Immunology Advance Access originally published online on September 19, 2005
International Immunology 2005 17(11):1463-1471; doi:10.1093/intimm/dxh324
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Active repression of IFN regulatory factor-1-mediated transactivation by IFN regulatory factor-4
1 Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
2 Laboratory of Biophysics, Department of Molecular Biology, Nara Institute of Science and Technology, Ikoma, Nara 630-0101, Japan
3 Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan
4 Second Department of Internal Medicine, Oita University Faculty of Medicine, Oita-gun, Oita 879-5593, Japan
5 Department of Host-Defense Biochemistry, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan
6 Division of Immunology, Department of Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
Correspondence to: T. Matsuyama; E-mail: tosim{at}net.nagasaki-u.ac.jp
IFN regulatory factor-4 (IRF-4) is a transcription factor that is involved in the development and the functions of lymphocytes, macrophages and dendritic cells. Despite their critical roles in immune system regulation, the target genes controlled by IRF-4 are poorly understood. In this study, we determined the consensus DNA-binding sequences preferred for IRF-4 by in vitro binding site selections. IRF-4 preferentially bound to the sequences containing tandem repeats of 5'-GAAA-3', flanked by CpC, in most cases. IRF-4 repressed the promoter bearing tandem copies of the selected binding sequence, while IRF-1 activated the same constructs. Interestingly, the IRF-1-dependent transactivation is inhibited in the presence of IRF-4, but not IRF-2. A series of deletion mutants of IRF-4 revealed that its DNA-binding domain was necessary and sufficient to antagonize the IRF-1-dependent transactivation. This dominant negative action of IRF-4 over IRF-1 was also observed in a natural promoter context, such as the TRAIL gene. These results indicate that IRF-4 acts as a natural antagonist against IRF-1 in immune cells.
Keywords: gene regulation, IRF-1, IRF-4, lymphocytes, transcription factors
Transmitting editor: H. Karasuyama
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