51. Cross-talk between Aryl Hydrocarbon Receptor and the Inflammatory Response: A ROLE FOR NUCLEAR FACTOR-κB*
- Author
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Vogel, Christoph FA, Khan, Elaine M, Leung, Patrick SC, Gershwin, M Eric, Chang, WL William, Wu, Dalei, Haarmann-Stemmann, Thomas, Hoffmann, Alexander, and Denison, Michael S
- Subjects
Lipopolysaccharides ,Biochemistry & Molecular Biology ,Polychlorinated Dibenzodioxins ,Knockout ,chemical and pharmacologic phenomena ,Response Elements ,Cell Line ,Mice ,Receptors ,Genetics ,Basic Helix-Loop-Helix Transcription Factors ,Cytochrome P-450 CYP1A1 ,2.1 Biological and endogenous factors ,Animals ,Humans ,Gene Regulation ,Aetiology ,Inflammation ,Mice, Knockout ,Medical And Health Sciences ,Inflammatory and immune system ,Transcription Factor RelA ,Dendritic Cells ,Biological Sciences ,biochemical phenomena, metabolism, and nutrition ,respiratory system ,respiratory tract diseases ,Gene Expression Regulation ,Receptors, Aryl Hydrocarbon ,Aryl Hydrocarbon ,Chemical Sciences ,Mutation ,bacteria ,Aryl Hydrocarbon Receptor ,NF-Kappa B ,Signal Transduction - 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. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
- Published
- 2013