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-Inducible Transcription Factor, IFN Consensus Sequence Binding Protein (ICSBP), Stimulates IL-12 p40 Expression in Macrophages
*
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and
Wistar Institute of Anatomy and Biology, Philadelphia, PA 19104
IL-12 is a cytokine that links innate and adaptive immunity. Its
subunit p40 is induced in macrophages following IFN-
/LPS
stimulation. Here we studied the role for IFN consensus sequence
binding protein (ICSBP), an IFN-/LPS-inducible transcription factor
of the IFN regulatory factor (IRF) family in IL-12 p40 transcription.
Macrophage-like cells established from
ICSBP-/- mice did not induce IL-12 p40
transcripts, nor stimulated IL-12 p40 promoter activity after
IFN-/LPS stimulation, although induction of other inducible genes
was normal in these cells. Transfection of ICSBP led to a marked
induction of both human and mouse IL-12 p40 promoter activities in
ICSBP+/+ and ICSBP-/- cells, even
in the absence of IFN-/LPS stimulation. Whereas IRF-1 alone was
without effect, synergistic enhancement of promoter activity was
observed following cotransfection of ICSBP and IRF-1. Deletion analysis
of the human promoter indicated that the Ets site, known to be
important for activation by IFN-/LPS, also plays a role in the ICSBP
activation of IL-12 p40. A DNA affinity binding assay revealed that
endogenous ICSBP is recruited to the Ets site through protein-protein
interaction. Last, transfection of ISCBP alone led to induction of the
endogenous IL-12 p40 mRNA in the absence of IFN- and LPS. Taken
together, our results show that ICSBP induced by IFN-/LPS, acts as a
principal activator of IL-12p40 transcription in
macrophages.
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J. Aliberti, O. Schulz, D. J. Pennington, H. Tsujimura, C. R. e Sousa, K. Ozato, and A. Sher Essential role for ICSBP in the in vivo development of murine CD8alpha + dendritic cells Blood, January 1, 2003; 101(1): 305 - 310. [Abstract] [Full Text] [PDF]
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S. Cao, J. Liu, M. Chesi, P. L. Bergsagel, I-C. Ho, R. P. Donnelly, and X. Ma Differential Regulation of IL-12 and IL-10 Gene Expression in Macrophages by the Basic Leucine Zipper Transcription Factor c-Maf Fibrosarcoma J. Immunol., November 15, 2002; 169(10): 5715 - 5725. [Abstract] [Full Text] [PDF]
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