title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated impairment of B cell differentiation involves dysregulation of paired box 5 (Pax5) isoform, Pax5a.
abstract: The persistent environmental contaminant and immunotoxicant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), markedly suppresses humoral immune responses. We recently reported impaired down-regulation of paired box 5 (Pax5), a repressor of B cell differentiation and concomitant suppression of the IgM response by TCDD in the murine CH12.LX B cell line. The objectives of the current study were to determine the impact of TCDD treatment on molecular outcomes characteristic of terminal B cell differentiation and to assess the role that Pax5 isoforms plays in the suppression of B cell differentiation by TCDD. In this study, we show that the highly abundant full-length Pax5 isoform, Pax5a, and at least two additional modestly expressed Pax5 isoforms were expressed in CH12.LX and splenic B cells. In lipopolysaccharide (LPS)-activated B cells, all of the identified Pax5 isoforms were synchronously down-regulated, and in the presence of TCDD cotreatment they were abnormally and synchronously elevated, suggesting a common mechanism of regulation. Furthermore, B cell differentiation markers X-box protein-1 and major histocompatibility complex class II showed that the levels to which Pax5 was derepressed by TCDD were sufficient to impair B cell differentiation and immunoglobulin gene expression. Confirming the involvement of Pax5, ectopic expression of Pax5a in the LPS-activated CH12.LX cells closely mimicked the suppression of the IgM response by TCDD. In summary, our results demonstrate that Pax5a has a critical role in both the TCDD-mediated impairment of B cell differentiation and the suppression of the humoral immune response.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Schneider
authors.forename: Maria A
authors.initials: MA
authors.lastname: Manzan
authors.forename: Robert B
authors.initials: RB
authors.lastname: Crawford
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004785:Environmental Pollutants / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D009687:Nuclear Proteins / Q000096:biosynthesis; D051757:PAX5 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D020033:Protein Isoforms; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D009687:Nuclear Proteins; D051757:PAX5 Transcription Factor; D000072317:Polychlorinated Dibenzodioxins; D020033:Protein Isoforms; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors