An IFN-gamma-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages.

TitleAn IFN-gamma-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages.
Publication TypeJournal Article
Year of Publication2000
AuthorsWang IM, Contursi C, Masumi A, Ma X, Trinchieri G, Ozato K
JournalJ Immunol
Date Published2000 Jul 01
KeywordsAnimals, Cell Line, Consensus Sequence, DNA-Binding Proteins, Drug Synergism, Gene Expression Regulation, Humans, Interferon Regulatory Factor-1, Interferon Regulatory Factor-2, Interferon Regulatory Factors, Interferon-gamma, Interleukin-12, Lipopolysaccharides, Macromolecular Substances, Macrophages, Mice, Mice, Knockout, Phosphoproteins, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ets, Repressor Proteins, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Transfection

IL-12 is a cytokine that links innate and adaptive immunity. Its subunit p40 is induced in macrophages following IFN-gamma/LPS stimulation. Here we studied the role for IFN consensus sequence binding protein (ICSBP), an IFN-gamma/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-gamma/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-gamma/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-gamma/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-gamma and LPS. Taken together, our results show that ICSBP induced by IFN-gamma/LPS, acts as a principal activator of IL-12p40 transcription in macrophages.

Alternate JournalJ Immunol
PubMed ID10861061

Weill Cornell Medicine Microbiology and Immunology 1300 York Avenue, Box 62 New York, NY 10065 Phone: (212) 746-6505 Fax: (212) 746-8587