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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated impairment of B cell differentiation involves dysregulation of paired box 5 (Pax5) isoform, Pax5a.

Authors: Schneider, Dina; Manzan, Maria A; Crawford, Robert B; Chen, Weimin; Kaminski, Norbert E

Published In J Pharmacol Exp Ther, (2008 Aug)

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.

PubMed ID: 18483191 Exiting the NIEHS site

MeSH Terms: Animals; Antibody Formation/drug effects; B-Lymphocytes/cytology; B-Lymphocytes/drug effects*; B-Lymphocytes/immunology; B-Lymphocytes/metabolism; Blotting, Western; Cell Differentiation/drug effects*; Cell Differentiation/immunology; Cell Line, Tumor; Cloning, Molecular; DNA-Binding Proteins/biosynthesis; Environmental Pollutants/toxicity*; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Gene Expression/drug effects; Immunoglobulin M/biosynthesis; Immunoglobulin M/genetics; Lipopolysaccharides/pharmacology; Lymphocyte Activation/drug effects; Mice; Mice, Inbred Strains; Nuclear Proteins/biosynthesis; PAX5 Transcription Factor/biosynthesis*; PAX5 Transcription Factor/genetics; PAX5 Transcription Factor/physiology; Polychlorinated Dibenzodioxins/toxicity*; Protein Isoforms; Regulatory Factor X Transcription Factors; Reverse Transcriptase Polymerase Chain Reaction; Spleen/cytology; Spleen/drug effects; Spleen/immunology; Transcription Factors

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