title: The AhR and NF-κB/Rel Proteins Mediate the Inhibitory Effect of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on the 3' Immunoglobulin Heavy Chain Regulatory Region.
abstract: Transcriptional regulation of the murine immunoglobulin (Ig) heavy chain gene (Igh) involves several regulatory elements including the 3'Igh regulatory region (3'IghRR), which is composed of at least 4 enhancers (hs3A, hs1.2, hs3B, and hs4). The hs1.2 and hs4 enhancers exhibit the greatest transcriptional activity and contain binding sites for several transcription factors including nuclear factor kappaB/Rel (NF-κB/Rel) proteins and the aryl hydrocarbon receptor (AhR). Interestingly, the environmental immunosuppressant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which potently inhibits antibody secretion, also profoundly inhibits 3'IghRR and hs1.2 enhancer activation induced by the B-lymphocyte activator lipopolysaccharide (LPS), but enhances LPS-induced activation of the hs4 enhancer. Within the hs1.2 and hs4 enhancers, the AhR binding site is in close proximity or overlaps an NF-κB/Rel binding site suggesting a potential reciprocal modulation of the 3'IghRR by AhR and NF-κB/Rel. The objective of the current study was to evaluate the role of NF-κB/Rel and the AhR on the 3'IghRR and its enhancers using the AhR ligand TCDD, the AhR antagonist CH223191, and toll-like receptor agonists LPS, Resiquimod (R848), or cytosine-phosphate-guanine-oligodeoxynucleotides (CpG). Utilizing the CH12.LX B-lymphocyte cell line and variants expressing either a 3'IghRR-regulated transgene reporter or an inducible IκBα (inhibitor kappa B-alpha protein) superrepressor (IκBαAA), we demonstrate an AhR- and NF-κB/Rel-dependent modulation of 3'IghRR and hs4 activity. Additionally, in mouse splenocytes or CH12.LX cells, binding within the hs1.2 and hs4 enhancer of the AhR and the NF-κB/Rel proteins RelA and RelB was differentially altered by the cotreatment of LPS and TCDD. These results suggest that the AhR and NF-κB/Rel protein binding profile within the 3'IghRR mediates the inhibitory effects of TCDD on Ig expression and therefore antibody levels.
authors.affiliation: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio 45435.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Salisbury
authors.affiliation: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio 45435 courtney.sulentic@wright.edu.
authors.forename: Courtney E W
authors.initials: CE
authors.lastname: Sulentic
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D050438:Genes, Immunoglobulin Heavy Chain; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D013997:Time Factors; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004785:Environmental Pollutants; D020672:I-kappa B Proteins; C500241:Ldlrap1 protein, mouse; C000606205:Nfkbia protein, mouse; D000072317:Polychlorinated Dibenzodioxins; C498144:Rela protein, mouse; C497594:Relb protein, mouse; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D051841:Transcription Factor RelB
keywords: 3′Igh regulatory region; NF-κB/Rel; TCDD; aryl hydrocarbon receptor; gene regulation; immunoglobulin; immunosuppression