Cross-talk between aryl hydrocarbon receptor and the inflammatory response: A role for nuclear factor-κB

Christoph F A Vogel, Elaine M. Khan, Patrick S Leung, M. Eric Gershwin, W. L William Chang, Dalei Wu, Thomas Haarmann-Stemmann, Alexander Hoffmann, Michael S. Denison

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

The aryl hydrocarbon receptor (AhR) is involved in the regulation of immune responses, T-cell differentiation, and immunity. Here, we show that inflammatory stimuli such as LPS induce the expression of AhR in human dendritic cells (DC) associated with an AhR-dependent increase of CYP1A1 (cytochrome P4501A1). In vivo data confirmed the elevated expression of AhR by LPS and the LPS-enhanced 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated induction of CYP1A1 in thymus of B6 mice. Inhibition of nuclear factor-κB (NF-κB) repressed both normal and LPS-enhanced, TCDD-inducible, AhR-dependent gene expression and canonical pathway control of RelA-regulated AhR-responsive gene expression. LPS-mediated induction of AhR was NF-κB-dependent, as shown in mouse embryonic fibroblasts (MEFs) derived from Rel null mice. AhR expression and TCDD-mediated induction of CYP1A1 was significantly reduced in RelA-deficient MEF compared with wild type MEF cells and ectopic expression of RelA restored the expression of AhR and induction of CYP1A1 in MEF RelA null cells. Promoter analysis of the human AhR gene identified three putative NF-κB-binding elements upstream of the transcription start site. Mutation analysis of the AhR promoter identified one NF-κB site as responsible for mediating the induction of AhR expression by LPS and electrophoretic shift assays demonstrated that this NF-κB motif is recognized by the RelA/p50 heterodimer. Our results show for the first time that NF-κB RelA is a critical component regulating the expression of AhR and the induction of AhR-dependent gene expression in immune cells illustrating the interaction of AhR and NF-κB signaling.

Original languageEnglish (US)
Pages (from-to)1866-1875
Number of pages10
JournalJournal of Biological Chemistry
Volume289
Issue number3
DOIs
StatePublished - Jan 17 2014

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Vogel, C. F. A., Khan, E. M., Leung, P. S., Gershwin, M. E., Chang, W. L. W., Wu, D., Haarmann-Stemmann, T., Hoffmann, A., & Denison, M. S. (2014). Cross-talk between aryl hydrocarbon receptor and the inflammatory response: A role for nuclear factor-κB. Journal of Biological Chemistry, 289(3), 1866-1875. https://doi.org/10.1074/jbc.M113.505578