The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages.
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.
Cao
Shanjin
S
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Liu
Jianguo
J
Song
Lihua
L
Ma
Xiaojing
X
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics*; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051257:Proto-Oncogene Proteins c-maf; D011519:Proto-Oncogenes; D011994:Recombinant Proteins / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; C495607:MAF protein, human; C495608:Maf protein, mouse; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D011994:Recombinant Proteins; D014157:Transcription Factors; D016753:Interleukin-10; D015847:Interleukin-4; D004247:DNA