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Departments of
* Microbiology and Immunology, and
Medicine, Weill Medical College of Cornell University, New York, NY 10021;
Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02115; and
Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
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-
B, 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.
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