2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the regulation of Pax5 in lipopolysaccharide-activated B cells.
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 (Igkappa), 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, Igkappa, 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, Igkappa, 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.
Department of Pharmacology and Toxicology, Michigan State University, Michigan 48824, USA.
Byung S
BS
Yoo
Darrell R
DR
Boverhof
Dina
D
Shnaider
Robert B
RB
Crawford
Timothy R
TR
Zacharewski
Norbert E
NE
Kaminski
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004785:Environmental Pollutants / Q000494:pharmacology*; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D051757:PAX5 Transcription Factor; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D007136:Immunoglobulins; D008070:Lipopolysaccharides; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D014157:Transcription Factors