The Aryl Hydrocarbon Receptor Regulates an Essential Transcriptional Element in the Immunoglobulin Heavy Chain Gene

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant that inhibits immunoglobulin (Ig) expression and Ig heavy (IgH) chain gene transcription. Transcription of the IgH gene involves several regulatory elements including the 3'lgh regulatory region (3'lghRR) which is composed of four enhancers (hs3A, hs1,2, hs4, and hs3B). Dioxin responsive elements (DRE) in the hs4 and hs1,2 enhancers of the 3lghRR that bind the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that regulates dioxin sensitive genes suggest that the 3'lghRR may be a transcriptional target of TCDD. The current study utilized an IgA secreting mouse B-cell line that stably expresses a γ 2b transgene regulated by the 3'lghRR (CH12.γ 2b-3'lghRR cells). Both shRNA knock down of AhR and an AhR antagonist (CH-223191) reduced TCDD-induced inhibition of endogenous IgA and the γ 2b transgene expression. With the growing number of immune-related disorders correlated with polymorphisms of the human hs1,2 enhancer, ubiquitously found AhR ligands, and sensitivity of human Ig expression to TCDD, our findings may provide indispensible information for human health risk assessment and insight into the development of therapeutic interventions for immune-related disease.