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Differential regulation of IL-12 and IL-10 gene expression in macrophages by the basic leucine zipper transcription factor c-Maf fibrosarcoma.

TitleDifferential regulation of IL-12 and IL-10 gene expression in macrophages by the basic leucine zipper transcription factor c-Maf fibrosarcoma.
Publication TypeJournal Article
Year of Publication2002
AuthorsCao S, Liu J, Chesi M, Bergsagel PLeif, Ho I-C, Donnelly RP, Ma X
JournalJ Immunol
Volume169
Issue10
Pagination5715-25
Date Published2002 Nov 15
ISSN0022-1767
KeywordsAnimals, Cell Line, Cells, Cultured, DNA-Binding Proteins, Down-Regulation, Female, Fetus, Fibrosarcoma, Gene Expression Regulation, Neoplastic, Humans, Interleukin-10, Interleukin-12, Interleukin-12 Subunit p35, Interleukin-12 Subunit p40, Interleukin-4, Leucine Zippers, Macrophage Activation, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes, NF-kappa B, Nucleoproteins, Promoter Regions, Genetic, Protein Structure, Tertiary, Protein Subunits, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-maf, Response Elements, Transcriptional Activation, Up-Regulation
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.

DOI10.4049/jimmunol.169.10.5715
Alternate JournalJ Immunol
PubMed ID12421951
Grant ListAI 45899 / AI / NIAID NIH HHS / United States
CA 79772 / CA / NCI NIH HHS / United States

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