IL-4-induced STAT6 suppresses IFN-gamma-stimulated STAT1-dependent transcription in mouse macrophages.
IL-4 suppresses the IFN-gamma-induced expression of the IFN regulatory factor-1 (IRF-1) gene, and this suppression is attenuated by increasing the amount of IFN-gamma. The effects of IFN-gamma and IL-4 on transcription of a reporter gene under control of a 1.3-kb fragment from the IRF-1 gene promoter or the STAT binding element (SBE) from this gene in the context of a heterologous promoter are similar to their effects on the endogenous IRF-1 gene. IFN-gamma-dependent transcription of reporter gene is suppressed by IL-4, but IL-4 alone has no trans-activating function. IL-4 treatment does not inhibit the tyrosine phosphorylation or nuclear translocation of IFN-gamma-activated STAT1. Rather, IFN-gamma and IL-4 independently activate STAT1 and STAT6, respectively, and both proteins bind to the IRF-1 SBE in homodimeric form. The affinity of STAT1 for the IRF-1 SBE is higher than the affinity of STAT6, as measured by competition with unlabeled oligonucleotide. These observations suggest that IL-4 may suppress IFN-gamma-stimulated transcription of the IRF-1 gene by activation of STAT6, which can compete with STAT1 for occupancy of the IRF-1 SBE when STAT1 levels are low. Suppression may be attenuated as the quantity of STAT1 relative to that of STAT6 increases in cells treated with increasing amounts of IFN-gamma and displaces STAT6.
Ohmori
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Y
Department of Immunology, The Cleveland Clinic Foundation, OH 44195, USA.
Hamilton
T A
TA
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000494:pharmacology*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma