title: Aryl hydrocarbon receptor signaling modifies Toll-like receptor-regulated responses in human dendritic cells.
abstract: Currently, it is not well understood how ligands of the aryl hydrocarbon receptor (AhR) modify inflammatory responses triggered by Toll-like receptor (TLR) agonists in human dendritic cells (DCs). Here, we show that AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the tryptophan derivatives 6-formylindolo[3,2-b] carbazole (FICZ), kynurenine (kyn), and the natural dietary compound indole-3-carbinol (I3C) differentially modify cytokine expression in human monocyte-derived DCs (MoDCs). The results show that TLR-activated MoDCs express higher levels of AhR and are more sensitive toward the effects of AhR ligands. Depending on the cytokine, treatment with AhR ligands led to a synergistic or antagonistic effect of the TLR-triggered response in MoDCs. Thus, activation of AhR increased the expression of interleukin (IL)-1β, but decreased the expression of IL-12A in TLR-activated MoDCs. Furthermore, TCDD and FICZ may have opposite effects on the expression of cytochrome P4501A1 (CYP1A1) in TLR8-activated MoDCs indicating that the effect of the specific AhR ligand may depend on the presence of the specific TLR agonist. Gene silencing showed that synergistic effects of AhR ligands on TLR-induced expression of IL-1β require a functional AhR and the expression of NF-κB RelB. On the other hand, repression of IL-12A by TCDD and FICZ involved the induction of the caudal type homeobox 2 (CDX2) transcription factor. Additionally, the levels of DC surface markers were decreased in MoDCs by TCDD, FICZ and I3C, but not by kyn. Overall, these data demonstrate that AhR modulates TLR-induced expression of cytokines and DC-specific surface markers in MoDCs involving NFκB RelB and the immune regulatory factor CDX2.
authors: Center for Health and the Environment, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.
authors: Sarah
authors: S
authors: Kado
authors: Center for Comparative Medicine, University of California, One Shields Avenue, Davis, CA 95616, USA.
authors: W L William
authors: WLW
authors: Chang
authors: Center for Health and the Environment, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.
authors: Aimy Nguyen
authors: AN
authors: Chi
authors: Center for Health and the Environment, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.
authors: Monika
authors: M
authors: Wolny
authors: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA.
authors: David M
authors: DM
authors: Shepherd
authors: Center for Health and the Environment, University of Montana, Missoula, MT, 59812, USA. cfvogel@ucdavis.edu.|Department of Environmental Toxicology, University of California, Davis, One Shields Avenue, Davis, CA, 95616, USA. cfvogel@ucdavis.edu.
authors: Christoph F A
authors: CFA
authors: Vogel
mesh_terms: D000071616:CDX2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007737:Kynurenine / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism
chemical_list: C111855:6-formylindolo(3,2-b)carbazole; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D002227:Carbazoles; D016207:Cytokines; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000072317:Polychlorinated Dibenzodioxins; C497593:RELB protein, human; D018336:Receptors, Aryl Hydrocarbon; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D051841:Transcription Factor RelB; D007737:Kynurenine
keywords: AhR; CDX2; Cytokines; Dendritic cells; NF-κB; TLR