Leukocyte Activation Induces Aryl Hydrocarbon Receptor Up-Regulation, DNA Binding, and Increased Cyp1a1Expression in the Absence of Exogenous Ligand
- 1Department of Pharmacology and Toxicology and Department of Pathology, Michigan State University, East Lansing, Michigan 48824 (R.B.C., N.E.K.) and 2Dow Chemical Company, Toxicology Research Laboratory, Midland, Michigan 48674 (M.P.H.)
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.
Footnotes
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Send reprint requests to: Dr. Norbert E. Kaminski, Dept. of Pharmacology and Toxicology, B-330 Life Sciences Bldg., Michigan State University, East Lansing, Michigan 48824. E-mail:kamins11{at}gems.msu.edu
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This work was supported in part by National Institutes of Health Grant ES02520.
- Abbreviations:
- AhR
- aryl hydrocarbon receptor
- ARNT
- aryl hydrocarbon receptor nuclear translocator
- DMSO
- dimethyl sulfoxide
- DRE
- dioxin-responsive enhancer
- EMSA
- electrophoretic mobility shift assay
- HAH
- halogenated aromatic hydrocarbon
- HEPES
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- hsp90
- 90-kDa heat shock protein
- Io
- ionomycin
- PMA
- phorbol-12-myristate-13-acetate
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
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- Received July 25, 1997.
- Accepted September 9, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
