LEUKOCYTE ACTIVATION INDUCES ARYL-HYDROCARBON RECEPTOR UP-REGULATION,DNA-BINDING, AND INCREASED CYP1A1 EXPRESSION IN THE ABSENCE OF EXOGENOUS LIGAND

The aryl hydrocarbon receptor (AhR) functions as a transcription facto r after ligand binding by halogenated aromatic hydrocarbons. 2,3,7,8-t etrachlorodibenzo-p-dioxin (TCDD), the most toxic halogenated aromatic hydrocarbon, is dependent on binding to the AhR to mediate a broad ra nge of toxic effects. Immune suppression is one of the most sensitive sequela associated with TCDD exposure, yet, paradoxically, resting leu kocytes express a relatively low amount of AhR. Here we report that ac tivation of leukocytes produced a 6-fold increase in AhR steady state mRNA levels and a concordant increase in AhR protein expression. Furth ermore, 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 d ioxin response element binding by the AhR in the presence of TCDD than in the absence of TCDD. These studies suggest that the mechanism resp onsible for the sensitivity of immunocompetent cells to TCDD may be di rectly associated with a marked increase in AhR expression, which acco mpanies leukocyte activation.