title: Diverse chemicals including aryl hydrocarbon receptor ligands modulate transcriptional activity of the 3'immunoglobulin heavy chain regulatory region.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a known disruptor of B-cell differentiation and a ligand for the aryl hydrocarbon receptor (AhR), induces binding of the AhR to dioxin responsive elements (DRE) in sensitive genes. The Ig heavy chain (IgH) gene is a sensitive target of TCDD and may be transcriptionally inhibited by TCDD through inhibition of the 3'IgH transcriptional regulatory region (3'IgHRR). While the 3'IgHRR contains binding sites for several transcription factors, two DRE motifs were also identified which may be responsible for TCDD-induced inhibition of 3'IgHRR activation and may implicate the AhR as an important regulator of IgH expression. The objectives of the present study were to determine if 3'IgHRR modulation is limited to TCDD or if structurally diverse chemicals (AhR ligands and non-AhR ligands) from environmental, industrial, dietary or pharmaceutical origin are also capable of modulating the 3'IgHRR and to verify a correlation between effects on a stable 3'IgHRR reporter and the endogenous IgH protein. Utilizing a CH12.LX mouse B-cell line that stably expresses a 3'IgHRR-regulated transgene, we identified an inhibition of both 3'IgHRR activation and IgH protein expression by the non-dioxin AhR activators indolo(3,2-b)carbazole, primaquine, carbaryl, and omeprazole which followed a rank order potency for AhR activation supporting a role of the AhR in the transcriptional regulation of the 3'IgHRR and IgH expression. However, modulation of the 3'IgHRR and IgH expression was not limited to AhR activators or to suppressive effects. Hydrogen peroxide and terbutaline had an activating effect and benzyl isothiocyanate was inhibitory. These chemicals are not known to influence the AhR signaling pathway but have been previously shown to modulate humoral immunity and/or transcription factors that regulate the 3'IgHRR. Taken together these results implicate the 3'IgHRR as a sensitive immunological target and are the first to identify altered 3'IgHRR activation by a diverse range of chemicals.
authors.affiliation: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Henseler
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Romer
authors.forename: Courtney E W
authors.initials: CE
authors.lastname: Sulentic
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D012721:Carbaryl / Q000633:toxicity; D002227:Carbazoles / Q000633:toxicity; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D007143:Immunoglobulin Heavy Chains / Q000187:drug effects* / Q000235:genetics; D007142:Immunoglobulin gamma-Chains / Q000235:genetics; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D009853:Omeprazole / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011319:Primaquine / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D015262:Xenobiotics / Q000737:chemistry / Q000633:toxicity*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012721:Carbaryl; D002227:Carbazoles; D007143:Immunoglobulin Heavy Chains; D007142:Immunoglobulin gamma-Chains; D008024:Ligands; D009853:Omeprazole; D000072317:Polychlorinated Dibenzodioxins; D011319:Primaquine; D018336:Receptors, Aryl Hydrocarbon; D015262:Xenobiotics; C484722:Ahr protein, mouse; C075954:indolo(3,2-b)carbazole