title: Leukocyte activation induces aryl hydrocarbon receptor up-regulation, DNA binding, and increased Cyp1a1 expression in the absence of exogenous ligand.
abstract: The aryl hydrocarbon receptor (AhR) functions as a transcription factor after ligand binding by halogenated aromatic hydrocarbons. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic halogenated aromatic hydrocarbon, is dependent on binding to the AhR to mediate a broad range of toxic effects. Immune suppression is one of the most sensitive sequela associated with TCDD exposure, yet, paradoxically, resting leukocytes express a relatively low amount of AhR. Here we report that activation of leukocytes produced a 6-fold increase in AhR steady state mRNA levels and a concordant increase in AhR protein expression. Furthermore, leukocyte activation induced AhR translocation, DNA binding to a dioxin response element, and CYP1A1 transcription in the absence of TCDD. Activated leukocytes exhibited an even greater enhancement of dioxin response element binding by the AhR in the presence of TCDD than in the absence of TCDD. These studies suggest that the mechanism responsible for the sensitivity of immunocompetent cells to TCDD may be directly associated with a marked increase in AhR expression, which accompanies leukocyte activation.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Crawford
authors.forename: M P
authors.initials: MP
authors.lastname: Holsapple
authors.forename: N E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology*; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000502:physiology
chemical_list: C497397:Arnt protein, mouse; D004268:DNA-Binding Proteins; D007476:Ionophores; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D015759:Ionomycin; D004247:DNA; D019363:Cytochrome P-450 CYP1A1; D013755:Tetradecanoylphorbol Acetate