The Th2 transcription factor c-Maf inhibits IL-12p35 gene expression in activated macrophages by targeting NF-kappaB nuclear translocation.
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.
Homma
Yoichiro
Y
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Cao
Shanjin
S
Shi
Xiaoyan
X
Ma
Xiaojing
X
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D005786:Gene Expression Regulation; D016753:Interleukin-10 / Q000378:metabolism; D053765:Interleukin-12 Subunit p35 / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism
D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; C495608:Maf protein, mouse; D016328:NF-kappa B; D051257:Proto-Oncogene Proteins c-maf; D020569:Proto-Oncogene Proteins c-rel; D016753:Interleukin-10