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Activation and repression of interleukin-12 p40 transcription by erythroid Kruppel-like factor in macrophages.

TitleActivation and repression of interleukin-12 p40 transcription by erythroid Kruppel-like factor in macrophages.
Publication TypeJournal Article
Year of Publication2004
AuthorsLuo Q, Ma X, Wahl SM, Bieker JJ, Crossley M, Montaner LJ
JournalJ Biol Chem
Volume279
Issue18
Pagination18451-6
Date Published2004 Apr 30
ISSN0021-9258
KeywordsAnimals, Binding Sites, Cells, Cultured, DNA-Binding Proteins, Gene Expression Regulation, Humans, Interleukin-12, Interleukin-12 Subunit p40, Kruppel-Like Transcription Factors, Macrophages, Mice, NF-kappa B, Promoter Regions, Genetic, Protein Subunits, Response Elements, Transcription Factors, Transcription, Genetic
Abstract

Transcription of interleukin (IL)-12 p40 in myeloid cells is attributed to the recruitment of multiple activated transcription factors such as nuclear factor kappaB (NFkappaB), CCAAT enhancer-binding protein beta, ets-2, PU.1, and so forth. We now provide the first description of the human erythroid Kruppel-like factor (EKLF) in human primary macrophages and identify the role of EKLF in IL-12 p40 expression. EKLF-specific binding to the CACCC element (-224 to -220) on the human IL-12 p40 promoter was observed in resting human primary macrophages. Functional analysis of the CACCC element revealed a dependent role for EKLF binding in activating IL-12 p40 transcription in resting RAW264.7 cells, whereas EKLF overexpression in the presence or absence of this element repressed IL-12 p40 transcription in interferon gamma/lipopolysaccharide-stimulated RAW264.7 cells. Murine endogenous IL-12 p40 mRNA was consistently induced by overexpressed EKLF in resting RAW264.7 cells, whereas EKLF suppressed IL-12 p40 expression in activated RAW264.7 cells. Modulation of nuclear binding activities at the IL-12 p40 NFkappaB half-site was induced by EKLF for down-regulation of IL-12 p40 transcription in activated RAW264.7 cells, but no effect of EKLF on NFkappaB activity was observed in resting RAW264.7 cells. Taken together, we identify EKLF as a transcription factor in macrophages able to regulate IL-12 p40 transcription depending on the cellular activation status. The bifunctional control of IL-12 p40 by EKLF and its modulation of NFkappaB support a potential function for this factor in orchestrating IL-12 p40 production in macrophages.

DOI10.1074/jbc.M400320200
Alternate JournalJ Biol Chem
PubMed ID14976188
PubMed Central IDPMC2965204
Grant ListR01 AI051225 / AI / NIAID NIH HHS / United States
R01 CA100223 / CA / NCI NIH HHS / United States
AI54891 / AI / NIAID NIH HHS / United States
R01 CA100223-01A1 / CA / NCI NIH HHS / United States
AI47760 / AI / NIAID NIH HHS / United States
R01 AI047760 / AI / NIAID NIH HHS / United States
AI34412 / AI / NIAID NIH HHS / United States
AI51225 / AI / NIAID NIH HHS / United States
R01 AI034412 / AI / NIAID NIH HHS / United States

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