IFN consensus sequence binding protein potentiates STAT1-dependent activation of IFNgamma-responsive promoters in macrophages.
IFNgamma, once called the macrophage-activating factor, stimulates many genes in macrophages, ultimately leading to the elicitation of innate immunity. IFNgamma's functions depend on the activation of STAT1, which stimulates transcription of IFNgamma-inducible genes through the GAS element. The IFN consensus sequence binding protein (icsbgamma or IFN regulatory factor 8), encoding a transcription factor of the IFN regulatory factor family, is one of such IFNgamma-inducible genes in macrophages. We found that macrophages from ICSBP-/- mice were defective in inducing some IFNgamma-responsive genes, even though they were capable of activating STAT1 in response to IFNgamma. Accordingly, IFNgamma activation of luciferase reporters fused to the GAS element was severely impaired in ICSBP-/- macrophages, but transfection of ICSBP resulted in marked stimulation of these reporters. Consistent with its role in activating IFNgamma-responsive promoters, ICSBP stimulated reporter activity in a GAS-specific manner, even in the absence of IFNgamma treatment, and in STAT1 negative cells. Indicative of a mechanism for this stimulation, DNA affinity binding assays revealed that endogenous ICSBP was recruited to a multiprotein complex that bound to GAS. These results suggest that ICSBP, when induced by IFNgamma through STAT1, in turn generates a second wave of transcription from GAS-containing promoters, thereby contributing to the elicitation of IFNgamma's unique activities in immune cells.
Contursi
C
C
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Wang
I M
IM
Gabriele
L
L
Gadina
M
M
O'Shea
J
J
Morse
H C
HC
Ozato
K
K
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000737:chemistry / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection; D000099185:Interferon Regulatory Factor-8
D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D000099185:Interferon Regulatory Factor-8; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse