Abstract
IL-12 is a principal activator of both innate and adaptive immunity against infectious agents and malignancies. Regulation of proinflammatory IL-12 gene expression in phagocytes by the anti-inflammatory cytokine IL-10 represents a major homeostatic process underlying host-pathogen and host-self interactions. Delineation of the signaling pathway of IL-10 is crucial to the understanding of immunological regulatory networks. In this study, we report that IL-10 and c-musculoaponeurotic fibrosarcoma (Maf) induce their mutual expression in inflammatory macrophages. We demonstrate that c-Maf is one of the physiological mediators of IL-10's immunosuppressive activities. When overexpressed, c-Maf selectively inhibits transcriptional activation of IL-12 p40 and p35 genes while potently activating IL-10 and IL-4 expression, potentially contributing to the development of a state of anti-inflammation and dichotomy of immunologic polarization. c-Maf induces changes in nuclear DNA-binding activities at multiple sites including the ets, GA-12, NF-kappaB, C/EBP, and AP-1 elements. Nonetheless, the essential c-Maf-responsive element appears to be located elsewhere. Inhibition of IL-12 p40 gene expression by c-Maf requires the N-terminal transactivation domain, suggesting an indirect mechanism of transcriptional inhibition involving the induction of an unidentified repressor. In c-Maf-deficient murine macrophages, IL-10 production is impaired. However, IL-10-mediated inhibition of IL-12 production remains intact, indicating the existence of alternative mediators in the absence of c-Maf, consistent with the observation that a functional AP-1 is required for this pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Line
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Cells, Cultured
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Down-Regulation / genetics
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Down-Regulation / immunology
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Female
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Fetus
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Fibrosarcoma / genetics
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Fibrosarcoma / immunology*
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Gene Expression Regulation, Neoplastic / immunology*
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Humans
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Interleukin-10 / biosynthesis
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Interleukin-10 / genetics*
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Interleukin-10 / physiology
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Interleukin-12 / antagonists & inhibitors
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Interleukin-12 / biosynthesis
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Interleukin-12 / genetics*
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Interleukin-12 / metabolism
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Interleukin-12 Subunit p35
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Interleukin-12 Subunit p40
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Interleukin-4 / physiology
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Leucine Zippers / genetics
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Macrophage Activation / genetics
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Macrophages / immunology*
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Macrophages / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Monocytes / immunology
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Monocytes / metabolism
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NF-kappa B / physiology
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Nucleoproteins / metabolism
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Promoter Regions, Genetic / immunology
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Protein Structure, Tertiary / genetics
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Protein Subunits / antagonists & inhibitors
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Protein Subunits / genetics
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Protein Subunits / metabolism
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-maf
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Response Elements / immunology
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Transcriptional Activation / genetics
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Transcriptional Activation / immunology
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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DNA-Binding Proteins
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IL12A protein, human
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Interleukin-12 Subunit p35
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Interleukin-12 Subunit p40
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MAF protein, human
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Maf protein, mouse
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NF-kappa B
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Nucleoproteins
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Protein Subunits
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-maf
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Interleukin-10
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Interleukin-12
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Interleukin-4