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TOXICOLOGY

2,3,7,8-Tetrachlorodibenzo-p-dioxin-Mediated Impairment of B Cell Differentiation Involves Dysregulation of Paired Box 5 (Pax5) Isoform, Pax5a

Department of Pharmacology and Toxicology (D.S., R.B.C., N.E.K.), Center for Integrative Toxicology (D.S., M.A.M., N.E.K.), Microbiology and Molecular Genetics (W.C.), Michigan State University, East Lansing, Michigan

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.

Address correspondence to: Dr. Norbert E. Kaminski, Center for Integrative Toxicology, 315 Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824. E-mail: kamins11{at}msu.edu

This article has been cited by other articles:

				D. Schneider, M. A. Manzan, B. S. Yoo, R. B. Crawford, and N. Kaminski Involvement of Blimp-1 and AP-1 Dysregulation in the 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated Suppression of the IgM Response by B Cells Toxicol. Sci., April 1, 2009; 108(2): 377 - 388. [Abstract] [Full Text] [PDF]