ToxSci Advance Access originally published online on November 4, 2003
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Toxicological Sciences 77, 272-279 (2004)
Copyright © 2004 by the Society of Toxicology
IMMUNOTOXICOLOGY |
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters the Regulation of Pax5 in Lipopolysaccharide-Activated B Cells
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* Department of Pharmacology and Toxicology,
Department of Biochemistry and Molecular Biology,
Institute for Environmental Toxicology, and
National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan 48824; and
¶ Department of Biology, Kyonggi University, Paldal-gu, Suwon-Si, Korea
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 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
), J chain, and X box protein-1 (XBP-1). Lipopolysaccharide (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 that 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, 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, 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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