The Th2 transcription factor c-Maf inhibits IL-12p35 gene expression in activated macrophages by targeting NF-kappaB nuclear translocation.

TitleThe Th2 transcription factor c-Maf inhibits IL-12p35 gene expression in activated macrophages by targeting NF-kappaB nuclear translocation.
Publication TypeJournal Article
Year of Publication2007
AuthorsHomma Y, Cao S, Shi X, Ma X
JournalJ Interferon Cytokine Res
Date Published2007 Sep
KeywordsActive Transport, Cell Nucleus, Animals, Cell Line, Cell Nucleus, Gene Expression Regulation, Interleukin-10, Interleukin-12 Subunit p35, Interleukin-12 Subunit p40, Lipopolysaccharides, Macrophage Activation, Macrophages, Mice, Mice, Knockout, NF-kappa B, Proto-Oncogene Proteins c-maf, Proto-Oncogene Proteins c-rel

The inflammatory response of macrophages to infectious agents is a highly dynamic and orchestrated process involving the release of a variety of inflammatory mediators, including interleukin-12 (IL-12), as a consequence of the recognition of the pathogens. Regulation of IL-12 gene expression by the anti-inflammatory cytokine IL-10 represents a major homeostatic process underlying host-pathogen and host-self interactions. Our group first reported that the Th2-specific transcription factor c-Maf is expressed also in macrophages treated with lipopolysaccharide (LPS) and IL-10. When overexpressed, c-Maf can potently suppress IL-12 production. However, c-Maf does not appear to be a physiologic regulator of IL-12p40 gene transcription because p40 production is not dysregulated in c-Maf-deficient macrophages. In this study, we investigated the role of c-Maf in regulation of the transcription of the p35 gene, which encodes the chain that is rate limiting in the synthesis of the heterodimeric IL-12. We report that c-Maf is a physiologic modulator of IL-12p35 gene expression and IL-12p70 production. We identify a novel NF-kappaB element within the proximal p35 promoter and show that c-Maf inhibits p35 transcription by antagonizing the effects of NF-kappaB, especially c-Rel, on p35 activation. It does so not by directly interacting with the target DNA but by interfering with the nuclear localization of NF-kappaB c-Rel. This study contributes to our understanding of the molecular basis of the homeostatic regulation of IL-12 production by c-Maf, which plays a dual role both in the function of antigen-presenting cells (APCs) and in T helper cell differentiation.

Alternate JournalJ Interferon Cytokine Res
PubMed ID17892401
Grant ListR01 CA100223 / CA / NCI NIH HHS / United States
R01 CA100223-01A1 / CA / NCI NIH HHS / United States
R01CA100223 / CA / NCI NIH HHS / United States

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