Regulation of interleukin 12 p40 expression through an NF-κB half-site

T. L. Murphy, M. G. Cleveland, P. Kulesza, J. Magram, K. M. Murphy

Research output: Contribution to journalArticle

426 Scopus citations

Abstract

Interleukin 12 (IL-12) is an inducible cytokine composed of 35- and 40- kDa subunits that is critical for promoting T helper type 1 development and cell-mediated immunity against pathogens. The 40-kDa subunit, expressed by activated macrophages and B cells, is induced by several pathogens in vivo and in vitro and is augmented or inhibited by gamma interferon (IFN-γ) or IL-10, respectively. Control of IL-12 p40 expression is therefore important for understanding resistance and susceptibility to a variety of pathogens, including Leishmania major and perhaps human immunodeficiency virus. In this report, we provide the first characterization of IL-12 p40 gene regulation in macrophages. We localize inducible activity of the promoter to the sequence -122GGGGAATTTTA-132 not previously recognized to bind Rel family transcription factors. We demonstrate binding of this sequence to NF-κB (p50/p65 and p50/c-Rel) complexes in macrophages activated by several p40- inducing pathogens and provide functional data to support a role for NF-κB family members in IL-12 p40 activation. Finally, we find that IFN-γ treatment of cells enhances this binding interaction, thus potentially providing a mechanism for IFN-γ augmentation of IL-12 production by macrophages.

Original languageEnglish
Pages (from-to)5258-5267
Number of pages10
JournalMolecular and cellular biology
Volume15
Issue number10
StatePublished - Jan 1 1995

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