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INFLAMMATION AND IMMUNOPHARMACOLOGY

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

Department of Pharmacology and Toxicology, Center for Integrative Toxicology, and National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan (C.E.W.S., W.Z., N.E.K.); and Korea Advanced Institute of Science and Technology, Daejeon, Korea (Y.J.N.)

Transcriptional regulation of the Ig heavy chain gene involves several regulatory elements, including the 3' 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 chain in B cells, and octamer have been identified within the 3' enhancer domains and are believed to be important in regulating 3' enhancer activity. We have identified an additional DNA binding motif, the dioxin-responsive element (DRE), which can contribute to 3' 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 µ 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' enhancer. Interestingly, TCDD enhances LPS-induced activation of the hs4 domain but profoundly inhibits LPS-induced activation of the complete 3' enhancer. Furthermore, site-directed mutational analysis demonstrated that a DRE and B 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' enhancer, which can mediate, at least in part, the effects of TCDD on the 3' enhancer and its domains, putatively contributing to a marked suppression of IgM production.

Address correspondence to: Dr. Norbert E. Kaminski, Department of Pharmacology and Toxicology, 315 National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824. E-mail: kamins11{at}msu.edu