2,3,7,8-Tetrachlorodibenzo-p-dioxin, an Exogenous Modulator of the 3′α Immunoglobulin Heavy Chain Enhancer in the CH12.LX Mouse Cell Line

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Transcriptional regulation of the Ig heavy chain gene involves several regulatory elements, including the 3' alpha enhancer, which is composed of four distinct regulatory domains. DNA binding sites for several transcription factors, including B cell-specific activator protein, nuclear factor for immunoglobulin kappa chain in B cells, and octamer have been identified within the 3' alpha enhancer domains and are believed to be important in regulating 3' alpha enhancer activity. We have identified an additional DNA binding motif, the dioxin-responsive element (DRE), which can contribute to 3' alpha enhancer regulation. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a known disrupter of B cell differentiation (i.e., decreased plasma cell formation, inhibition of mu heavy chain expression, and suppression of IgM secretion), induces binding of the aryl hydrocarbon receptor (AhR) nuclear complex to DREs. TCDD also induces AhR binding to the hypersensitive (hs) 4 domain of the 3' alpha enhancer. Interestingly, TCDD enhances LPS-induced activation of the hs4 domain but profoundly inhibits LPS-induced activation of the complete 3' alpha enhancer. Furthermore, site-directed mutational analysis demonstrated that a DRE and kappaB element in the hs4 domain is modulated by TCDD in lipopolysaccharide-activated B cells. We propose that the AhR is a novel transcriptional regulator of the 3' alpha enhancer, which can mediate, at least in part, the effects of TCDD on the 3' alpha enhancer and its domains, putatively contributing to a marked suppression of IgM production.
Publisher
Amer Soc Pharmacology Experimental Therapeutics
Issue Date
2004-04
Language
English
Article Type
Article
Citation

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, v.309, no.1, pp.71 - 78

ISSN
0022-3565
DOI
10.1124/jpet.103.059493
URI
http://hdl.handle.net/10203/78356
Appears in Collection
RIMS Journal Papers
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