The Protooncogene c-Maf Is an Essential Transcription Factor for IL-10 Gene Expression in Macrophages
Open accessAbstract
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.
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WWOX and MAF were both prioritized for the WWOX locus, with MAF highly expressed in microglia and WWOX expressed most highly in astrocytes and neurons.
“WWOX and MAF, which surround an intergenic signal in an obesity associated locus91, were both prioritized for the WWOX locus, with MAF, another important regulator of macrophages92,93, being highly expressed in microglia in the Brain RNA-seq database, and WWOX, a high-density-lipoprotein cholesterol and triglyceride–associated gene94,95, being expressed most highly in astrocytes and neurons.”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [93]
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- Authors
- Cao, S., Liu, J., Song, L., & Ma, X.
- Affiliations
- Cornell University (US)
- Department of Microbiology and Immunology, Weill Medical College of Cornell University , New York, NY 10021
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-03
- Volume
- 174
- Issue
- 6
- Pages
- 3484-3492
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC2955976
- OpenAlex
- W2095592851
- Cited by
- 244
- References
- 62
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 4 · 2023: 10 · 2022: 15 · 2021: 17 · 2020: 19 · 2019: 16 · 2018: 11 · 2017: 10 · 2016: 9 · 2015: 14 · 2014: 13 · 2013: 12 · 2012: 9
- FWCI
- 4.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA100223, R01CA100223)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- c-Maf, IL-10 gene expression, macrophages, transcriptional regulation, IL-10 promoter, enhancers, IL-4, lipopolysaccharide stimulation, monocytes, immune regulation, bZIP transcription factors
- MeSH terms
- Animals, Base Sequence, Binding Sites, Cell Line, DNA, DNA-Binding Proteins, Enhancer Elements, Genetic, Humans, Lipopolysaccharides, Macrophages, Molecular Sequence Data, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogenes, Recombinant Proteins, Transcription Factors, Transfection, Interleukin-4, Gene Expression, Interleukin-10, Mice, Knockout, Proto-Oncogene Proteins c-maf, Mice, In Vitro Techniques
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