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The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages.

TitleThe protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages.
Publication TypeJournal Article
Year of Publication2005
AuthorsCao S, Liu J, Song L, Ma X
JournalJ Immunol
Volume174
Issue6
Pagination3484-92
Date Published2005 Mar 15
ISSN0022-1767
KeywordsAnimals, Base Sequence, Binding Sites, Cell Line, DNA, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression, Humans, In Vitro Techniques, Interleukin-10, Interleukin-4, Lipopolysaccharides, Macrophages, Mice, Mice, Knockout, Molecular Sequence Data, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-maf, Proto-Oncogenes, Recombinant Proteins, Transcription Factors, Transfection
Abstract

IL-10 is an important immunoregulatory factor. However, our understanding of IL-10 gene regulation remains very limited. In this study, following up on our previous novel finding that the protooncogene c-Maf of the basic leucine zipper family of transcription factors is expressed in monocytes and macrophages, we investigate the role of c-Maf in the transcriptional regulation of IL-10 and the underlying molecular mechanism in macrophages. c-Maf-null macrophages exhibit strongly impaired IL-10 protein production and mRNA expression upon LPS stimulation. Ectopic expression of c-Maf stimulates not only exogenously transfected IL-10 promoter-driven luciferase activity in a dose-dependent manner but also enhances endogenous IL-10 gene expression stimulated by LPS. Both in vitro and in vivo experiments identify a c-Maf response element localized to nucleotides -196/-184 relative to the transcription initiation site in the IL-10 promoter. This site represents an atypical 12-O-tetradecanoate-13-acetate-responsive element for musculoaponeurotic fibrosarcoma recognition and functions as an enhancer element in a heterologous and orientation-independent manner. Furthermore, c-Maf is expressed constitutively in resting monocytes/macrophages. IL-4 can up-regulate c-Maf expression, its binding to IL-10 promoter, and dose dependently enhance IL-10 production induced by LPS; moreover, IL-4 failed to enhance LPS-induced IL-10 production in c-Maf-null macrophages. Taken together, these data demonstrate that c-Maf is an indispensable yet constitutive transcription factor for IL-10 gene expression in LPS-activated macrophages, and IL-4 modulates IL-10 production in inflammatory macrophages likely via its ability to induce c-Maf expression. Thus, this study uncovers a novel and important function of c-Maf in macrophages and elucidates its transcriptional mechanism in the regulation of IL-10 gene expression.

DOI10.4049/jimmunol.174.6.3484
Alternate JournalJ Immunol
PubMed ID15749884
PubMed Central IDPMC2955976
Grant ListR01 CA100223 / CA / NCI NIH HHS / United States
R01 CA100223-01A1 / CA / NCI NIH HHS / United States
CA100223 / CA / NCI NIH HHS / United States

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