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Differential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-gamma-primed IL-12 production by IFN regulatory factor 1.

TitleDifferential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-gamma-primed IL-12 production by IFN regulatory factor 1.
Publication TypeJournal Article
Year of Publication2003
AuthorsLiu J, Cao S, Herman LM, Ma X
JournalJ Exp Med
Volume198
Issue8
Pagination1265-76
Date Published2003 Oct 20
ISSN0022-1007
KeywordsAnimals, Base Sequence, Cell Line, DNA-Binding Proteins, Gene Expression Regulation, Interferon Regulatory Factor-1, Interferon-gamma, Interleukin-12, Interleukin-12 Subunit p35, Interleukin-12 Subunit p40, Lipopolysaccharides, Mice, Molecular Sequence Data, NF-kappa B, Phosphoproteins, Promoter Regions, Genetic, Protein Subunits, Response Elements, Signal Transduction, Transfection
Abstract

Interleukin (IL)-12 is a heterodimeric cytokine consisting of the p40 and p35 chains encoded on separate chromosomes. Coordinated expression of the two constituent genes is crucial for appropriate immune responses in timing, location, and magnitude. Interferon (IFN)-gamma priming of IL-12 production by macrophages represents an important physiological process in vivo for escalated cellular response to microbial infections. We provide evidence that IFN regulatory factor (IRF)-1-deficient macrophages have a selective impairment in mRNA synthesis of IL-12 p35 but not the p40 gene, and a strong deficiency in the production of IL-12 p70 but not p40. We demonstrate that the levels of IL-12 p35 protein stimulated by IFN-gamma and lipopolysaccharide (LPS) correspond to those of its mRNA, and that the nuclear factor kappaB signaling pathway is essential for the induction of IL-12 p35 transcription by LPS. IRF-1 plays a major role in the transcriptional activation of the IL-12 p35 gene, but not of the p40 gene, by physically interacting with an inverted IRF element within the IL-12 p35 promoter upon IFN-gamma activation. Moreover, IRF-1-mediated transcriptional activation of the p35 promoter requires the cooperation of two adjacent Sp1 elements. Thus, IRF-1 acts as a critical component of IFN-gamma signaling in the selective activation of IL-12 p35 transcription in synergy with LPS-mediated events.

DOI10.1084/jem.20030026
Alternate JournalJ Exp Med
PubMed ID14568984
PubMed Central IDPMC2194226
Grant ListR01 AI045899 / AI / NIAID NIH HHS / United States
AI-045899 / AI / NIAID NIH HHS / United States
CA-79772 / CA / NCI NIH HHS / United States

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