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Synergistic activation of interleukin-12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein.

TitleSynergistic activation of interleukin-12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein.
Publication TypeJournal Article
Year of Publication2004
AuthorsLiu J, Guan X, Tamura T, Ozato K, Ma X
JournalJ Biol Chem
Volume279
Issue53
Pagination55609-17
Date Published2004 Dec 31
ISSN0021-9258
KeywordsAnimals, Base Sequence, Blotting, Western, Cell Line, Cell Nucleus, Chromatin Immunoprecipitation, DNA, DNA-Binding Proteins, Dose-Response Relationship, Drug, Enzyme-Linked Immunosorbent Assay, Humans, Immunoprecipitation, Inflammation, Interferon Regulatory Factor-1, Interferon Regulatory Factors, Interferons, Interleukin-12, Interleukin-12 Subunit p35, Interleukin-12 Subunit p40, Lipopolysaccharides, Macrophages, Mice, Mice, Transgenic, Models, Biological, Molecular Sequence Data, Mutation, Phosphoproteins, Promoter Regions, Genetic, Protein Binding, Protein Subunits, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Ribonucleases, RNA, Messenger, Sequence Homology, Nucleic Acid, Time Factors, Transcription, Genetic, Transcriptional Activation, Transfection
Abstract

Interferon regulatory factor-1 (IRF-1) and interferon consensus sequence-binding protein (ICSBP or IRF-8) are two members of the IRF family of transcription factors that play critical roles in interferon signaling in a wide range of host responses to infection and malignancy. Interleukin-12 (IL-12) is a key factor in the induction of innate resistance and generation of T helper type 1 cells and cytotoxic T lymphocytes. In this work, we find that ICSBP-deficient macrophages are highly defective in the production of IL-12. The defect is also observed at the level of IL-12 p40 and p35 mRNA expression. Transcriptional analyses revealed that ICSBP is a potent activator of the IL-12 p35 gene. It acts through a site localized to -226 to -219, named ICSBP-response element (ICSBP-RE), in the human IL-12 p35 promoter through physical association with IRF-1 both in vitro and in vivo. Co-expression of ICSBP and IRF-1 synergistically stimulates the IL-12 p35 promoter activity. Mutations at the ICSBP-RE results in the loss of protein binding as well as transcriptional activation by ICSBP alone or together with IRF-1. This study provides novel mechanistic information on how signals initiated during innate and adaptive immune responses synergize to yield greater IL-12 production and sustained cellular immunity.

DOI10.1074/jbc.M406565200
Alternate JournalJ Biol Chem
PubMed ID15489234
Grant ListAI 045899 / AI / NIAID NIH HHS / United States
CA 79772 / CA / NCI NIH HHS / United States

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