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ToxSci Advance Access published online on November 4, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh013
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received August 26, 2003; accepted October 2, 2003
© 2003 Society of Toxicology

Immunotoxicology

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters the Regulation of Pax5 in Lipopolysaccharide-Activated B Cells

Byung S. Yoo 1, Darrell R. Boverhof 2, Dina Shnaider 3, Robert B. Crawford 4, Timothy R. Zacharewski 5, and Norbert E. Kaminski 6*

1 Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, 48824 USA; Department of Biology, Kyonggi University, Paldal-gu, Suwon-Si, KOREA
2 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824 USA; Institute for Environmental Toxicology, Michigan State University, East Lansing, MI, 48824 USA
3 Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, 48824 USA; Institute for Environmental Toxicology, Michigan State University, East Lansing, MI, 48824 USA
4 Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, 48824 USA
5 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824 USA; Institute for Environmental Toxicology, Michigan State University, East Lansing, MI, 48824 USA; National Food Safety & Toxicology Center, Michigan State University, East Lansing, MI, 48824 USA
6 Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, 48824 USA; Institute for Environmental Toxicology, Michigan State University, East Lansing, MI, 48824 USA; National Food Safety & Toxicology Center, Michigan State University, East Lansing, MI, 48824 USA

* To whom correspondence should be addressed. E-mail: kamins11{at}msu.edu.


  Abstract

The environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), produces a profound suppression of the primary immunoglobulin-M (IgM) antibody response. The suppression of IgM production by TCDD can occur through direct interactions with the B cell, is aryl hydrocarbon receptor-dependent, and is mediated through alterations in the differentiation of B cells into the plasma cells. The objective of the present investigation was to characterize the effects of TCDD on the regulation of Pax5, a crucial repressor of B cell differentiation and four downstream targets that are directly regulated by Pax5 and involved in immunoglobulin regulation, immunoglobulin heavy chain (IgH), kappa light chain (Ig{kappa}), J chain and X box protein-1 (XBP-1). LPS-activation of aryl hydrocarbon receptor-expressing CH12.LX cells induced B cell differentiation and robust immunoglobulin secretion that was markedly (~50%) suppressed in the presence of 10 nM TCDD. Kinetic studies show that LPS-activation induced a time-dependent decrease in Pax5 mRNA levels, protein and DNA binding activity during a 72 h culture period which was almost completely blocked in the presence of TCDD. Concomitant with the time-dependent down-regulation of Pax5 in LPS-activated control CH12.LX cells, a reciprocal induction of IgH, Ig{kappa}, J chain mRNA levels and cellular XBP-1 was observed. Conversely, and consistent with the absence of Pax5 down-regulation associated with TCDD treatment, IgH, Ig{kappa}, J chain mRNA and XBP-1 protein were persistently repressed in LPS-activated CH12.LX cells. Collectively, these studies demonstrate the involvement of altered Pax5 regulation in the suppression of the primary IgM antibody response by TCDD.

Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin, Pax5, X-box-binding-protein-1, immunoglobulin heavy chain, immunoglobulin kappa light chain, B cell .


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