EBV-induced gene 3 transcription is induced by TLR signaling in primary dendritic cells via NF-κB activation

Stefan Wirtz, Christoph Becker, Massimo C. Fantini, Edward E. Nieuwenhuis, Ingrid Tubbe, Peter R. Galle, Hans Jörg Schild, Mark Birkenbach, Richard S. Blumberg, Markus F. Neurath

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

Abstract

The EBV-induced gene 3 (EBI3) is expressed in dendritic cells (DCs) and part of the cytokine IL-27 that controls Th cell development. However, its regulated expression in DCs is poorly understood. In the present study we demonstrate that EBI3 is expressed in splenic CD8-, CD8+, and plasmacytoid DC subsets and is induced upon TLR signaling. Cloning and functional analysis of the EBI3 promoter using in vivo footpriniing and mutagenesis showed that stimulation via TLR2, TLR4, and TLR9 transactivated the promoter in primary DCs via NF-κB and Ets binding sites at -90 and -73 bp upstream of the transcriptional start site, respectively. Furthermore, we observed that NF-κB p50/p65 and PU.1 were sufficient to transactivate the EBI3 promoter in EBD-deficient 293 cells. Finally, induced EBI3 gene expression in DCs was reduced or abrogated in TLR-2/TLR4, TLR9, and MyD88 knockout mice, whereas both basal and inducible EBI3 mRNA levels in DCs were strongly suppressed in NF-κB p50-deficient mice. In summary, these data suggest that EBI3 expression in DCs is transcriptionally regulated by TLR signaling via MyD88 and NF-κB. Thus, EBI3 gene transcription in DCs is induced rapidly by TLR signaling during innate immune responses preceding cytokine driven Th cell development.

Original languageEnglish (US)
Pages (from-to)2814-2824
Number of pages11
JournalJournal of Immunology
Volume174
Issue number5
DOIs
StatePublished - Mar 1 2005

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