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.
Yoo
Byung S
BS
Department of Pharmacology and Toxicology, Michigan State University, Michigan 48824, USA.
Boverhof
Darrell R
DR
Shnaider
Dina
D
Crawford
Robert B
RB
Zacharewski
Timothy R
TR
Kaminski
Norbert E
NE
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