Differential regulation of IL-12 and IL-10 gene expression in macrophages by the basic leucine zipper transcription factor c-Maf fibrosarcoma.
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.
Cao
Shanjin
S
Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Liu
Jianguo
J
Chesi
Marta
M
Bergsagel
Peter Leif
PL
Ho
I-Cheng
IC
Donnelly
Raymond P
RP
Ma
Xiaojing
X
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D005333:Fetus; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D015847:Interleukin-4 / Q000502:physiology; D016350:Leucine Zippers / Q000235:genetics; D008262:Macrophage Activation / Q000235:genetics; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D009698:Nucleoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051257:Proto-Oncogene Proteins c-maf; D020218:Response Elements / Q000276:immunology; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D004268:DNA-Binding Proteins; C508858:IL12A protein, human; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; C495607:MAF protein, human; C495608:Maf protein, mouse; D016328:NF-kappa B; D009698:Nucleoproteins; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4