The aryl hydrocarbon receptor regulates an essential transcriptional element in the immunoglobulin heavy chain gene.
Ig heavy chain (Igh) transcription involves several regulatory elements including the 3'Igh regulatory region (3'IghRR). 3'IghRR activity is modulated by several transcription factors, including NF-κB and AP-1 and potentially the aryl hydrocarbon receptor (AhR). The prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibits antibody secretion and 3'IghRR activity. However, the exact mechanism is unknown and TCDD can modulate NF-κB and AP-1 in an AhR-independent manner. To determine if the AhR is a significant regulator of the 3'IghRR, we utilized a mouse B-cell line that stably expresses a 3'IghRR-regulated transgene and either an AhR antagonist or shRNA targeting the AhR. Disruption of the AhR pathway reversed TCDD-induced suppression of the 3'IghRR-regulated transgene and of endogenous Ig demonstrating a biologically significant effect of the AhR on 3'IghRR activation. Altered human 3'IGHRR activity by AhR ligands, which include dietary, environmental, and pharmaceutical chemicals, may have significant implications to human diseases previously associated with the 3'IGHRR.
Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
Michael J
MJ
Wourms
Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA. Electronic address: courtney.sulentic@wright.edu.
Courtney E W
CE
Sulentic
D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D034622:RNA Interference; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013723:Teratogens / Q000494:pharmacology; D014158:Transcription, Genetic
C511621:2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide; D001391:Azo Compounds; D007143:Immunoglobulin Heavy Chains; D000072317:Polychlorinated Dibenzodioxins; D011720:Pyrazoles; D018336:Receptors, Aryl Hydrocarbon; D013723:Teratogens; D019363:Cytochrome P-450 CYP1A1
3′Igh regulatory region; Aryl hydrocarbon receptor; B cells; Dioxin, Gene regulation; Immunoglobulin expression; Immunoglobulin heavy chain; Immunosuppression; TCDD; Transcriptional enhancers