Journal Article

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

Byung S. Yoo, Darrell R. Boverhof, Dina Shnaider, Robert B. Crawford, Timothy R. Zacharewski and Norbert E. Kaminski

in Toxicological Sciences

Volume 77, issue 2, pages 272-279
Published in print February 2004 | ISSN: 1096-6080
Published online February 2004 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfh013
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters the Regulation of Pax5 in Lipopolysaccharide-Activated B Cells

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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 (Igκ), 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, Igκ, 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, Igκ, 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.

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

Journal Article.  6219 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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