Simultaneous in vivo time course and dose response evaluation for TCDD-induced impairment of the LPS-stimulated primary IgM response.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent suppressor of humoral immunity but the specific molecular mechanisms responsible for immunosuppression by TCDD are poorly understood. In vivo and in vitro studies of the primary humoral IgM response demonstrated that the B cell is a sensitive cell type to modulation by TCDD. We hypothesized that in vivo administration of TCDD disrupts expression of transcription factors controlling B cell to plasma cell differentiation. Female C57BL6 mice were treated with a single dose of TCDD (3, 10, or 30 microg/kg) and/or vehicle (sesame oil). On day 4 post-TCDD administration mice were sensitized with 25 microg lipopolysacchride (LPS) by intraperitioneal injection to stimulate an immune response. Splenocytes were isolated on subsequent days following LPS, up to 3 days post-LPS, and the expression of IgM, XBP-1, PAX5, BCL-6, and Blimp-1 was assessed. TCDD treatment dose-dependently suppressed LPS-induced IgM antibody-forming cell number, which was correlated with decreased frequency of CD19+ CD138+ cells. Gene expression analysis revealed that TCDD caused a dose-dependent suppression of Igmicro chain, Igkappa chain, IgJ chain, XBP-1, and Blimp-1. TCDD also dose-dependently suppressed LPS-stimulated increases in Blimp-1 protein expression in CD19+ B cells. The deregulation of Blimp-1 expression by TCDD provides a partial explanation for the concomitant suppression of the IgM response and confirms previous observations established in vitro.
North
Colin M
CM
Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824.
Crawford
Robert B
RB
Lu
Haitian
H
Kaminski
Norbert E
NE
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D007075:Immunoglobulin M / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D000072317:Polychlorinated Dibenzodioxins; C513258:Prdm1 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D000074462:Positive Regulatory Domain I-Binding Factor 1
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