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National Institute of Environmental Health Sciences

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Publication Detail

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.

Authors: Sulentic, C E; Holsapple, M P; Kaminski, N E

Published In J Pharmacol Exp Ther, (2000 Nov)

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.

PubMed ID: 11046109 Exiting the NIEHS site

MeSH Terms: Animals; B-Lymphocytes/drug effects; B-Lymphocytes/immunology; B-Lymphocytes/metabolism; Binding Sites; Cytochrome P-450 CYP1A1/biosynthesis; Enhancer Elements, Genetic/drug effects; Enhancer Elements, Genetic/physiology; Environmental Pollutants/toxicity*; Enzyme Induction; Gene Expression Regulation/drug effects*; Immunoglobulin M/biosynthesis*; Immunoglobulin M/genetics; Immunoglobulin mu-Chains/biosynthesis; Immunoglobulin mu-Chains/genetics; Ligands; Lipopolysaccharides/antagonists & inhibitors; Lipopolysaccharides/immunology; Mice; Mice, Inbred BALB C; NF-kappa B/metabolism; Receptors, Aryl Hydrocarbon/metabolism; Receptors, Aryl Hydrocarbon/physiology*; Response Elements/drug effects; Response Elements/physiology; Signal Transduction/drug effects; Signal Transduction/physiology; Structure-Activity Relationship; Tetrachlorodibenzodioxin/analogs & derivatives; Tetrachlorodibenzodioxin/toxicity*; Transcription, Genetic/drug effects

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