title: Putative link between transcriptional regulation of IgM expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin and the aryl hydrocarbon receptor/dioxin-responsive enhancer signaling pathway.
abstract: The B-cell, a major cellular component of humoral immunity, has been identified as a sensitive target of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD). The actual molecular mechanism responsible for the immunotoxic effects produced by TCDD is unclear; however, many of the biological effects produced by TCDD are thought to be mediated by the aryl hydrocarbon receptor (AhR). Using the CH12.LX B-cell line, the present studies show that inhibition of mu gene expression and IgM protein secretion by polychlorinated dibenzo-p-dioxin congeners follow a structure-activity relationship for AhR binding. Furthermore, these effects may be mediated by the two dioxin-responsive enhancer (DRE)-like sites that were identified within the Ig heavy chain 3'alpha-enhancer. Electrophoretic mobility shift assay-Western analysis demonstrated TCDD-induced binding of the AhR nuclear complex to both DRE-like sites as well as TCDD-induced binding of several nuclear factor-kappa B/Rel proteins to a kappa B site, which overlaps one of the DRE-like sites. Interestingly, kappa B binding in the AhR-deficient BCL-1 B-cells was also induced by TCDD, demonstrating an AhR-independent effect of TCDD on kappa B binding. Taken together, these results support an AhR/DRE-mediated mechanism for TCDD-induced inhibition of IgM expression.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Sulentic
authors.forename: M P
authors.initials: MP
authors.lastname: Holsapple
authors.forename: N E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004742:Enhancer Elements, Genetic / Q000187:drug effects / Q000502:physiology; D004785:Environmental Pollutants / Q000633:toxicity*; D004790:Enzyme Induction; D005786:Gene Expression Regulation / Q000187:drug effects*; D007075:Immunoglobulin M / Q000096:biosynthesis* / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000096:biosynthesis / Q000235:genetics; D008024:Ligands; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism / Q000502:physiology*; D020218:Response Elements / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004785:Environmental Pollutants; D007075:Immunoglobulin M; D007148:Immunoglobulin mu-Chains; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1