Down-regulation of Major Histocompatibility ComplexQ1b Gene Expression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Liqun Dong,Qiang Ma,James P Whitlock

doi:10.1074/jbc.272.47.29614

Abstract

Abstract We analyzed mouse hepatoma cells using differential display to discover new genes that respond to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We identified a class I major histocompatibility complex (MHC) gene, which we designated as MHC Q1 b, whose expression decreases in the presence of TCDD. TCDD-induced down-regulation of MHCQ1 b requires both the aromatic hydrocarbon receptor and the aromatic hydrocarbon receptor nuclear translocator, transcription factors that up-regulate other genes in response to TCDD. Down-regulation of MHC Q1 b by TCDD appears to involve both transcriptional and post-transcriptional regulatory events; the post-transcriptional destabilization of MHCQ1 b mRNA is probably a secondary response to TCDD. Our findings reveal new mechanistic aspects of gene regulation by TCDD. In addition, our observations suggest a mechanism that might account for some of TCDD’s immunotoxic effects.

Highlights

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)1 represents the prototype for a class of structurally related halogenated aromatic hydrocarbons, including polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls
TCDD binds to aromatic hydrocarbon receptor (AhR) in the cytoplasm; subsequently, the liganded AhR enters the nucleus and heterodimerizes with a second basic helix-loop-helix protein known as the AhR nuclear translocator (Arnt)
We show that TCDD down-regulates the expression of a class I major histocompatibility complex (MHC) gene, which we designate as MHC Q1b, and we examine the mechanism of the down-regulation

Summary

Introduction

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)1 represents the prototype for a class of structurally related halogenated aromatic hydrocarbons, including polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls. To identify an MHC Q1b-specific probe, we synthesized several probes by PCR using cDNA clones as templates, and we analyzed RNA from uninduced and TCDD-induced wild-type cells. Our results indicate that Q1b mRNA is differentially spliced, that the 2.7-kb transcript represents most MHC Q1b mRNA, which contains unspliced introns, and that MHC Q1b mRNA is down-regulated by TCDD.

Results

Conclusion