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ToxSci Advance Access published online on July 25, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg199
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received April 30, 2003; accepted July 13, 2003
© 2003 Society of Toxicology

Immunotoxicology

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters the Regulation and Post-Translational Modification of p27kip1 in Lipopolysaccharide-Activated B Cells

Robert B. Crawford 1, Courtney E. W. Sulentic 1, Byung S. Yoo 2, and Norbert E. Kaminski 1*

1 Department of Pharmacology & Toxicology, National Food Safety & Toxicology Center, Michigan State University, East Lansing, MI, USA
2 Department of Biology, Kyonggi University, Paldal-gu, Suwon-Si, Korea

* To whom correspondence should be addressed. E-mail: kamins11{at}msu.edu.


  Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters B cell differentiation as evidenced by a marked decrease in immunoglobulin M (IgM) secretion and in the number of antibody forming cells (AFC) induced by antigenic stimulation. The objective of the present studies was to evaluate the effect of TCDD on the level of p27kip1, a cyclin dependent kinase inhibitor, which is a critical regulator of cellular differentiation. In the well-characterized B cell line, CH12.LX, a modest decrease in p27kip1 was observed during the initial 24 h post-LPS activation, which then gradually increased above background at 48 and 72 h. Conversely, in the presence of TCDD, p27kip1 was not induced and remained unchanged from LPS-unstimulated cells throughout the entire 72 h period post-LPS activation. In addition, Western blotting revealed that TCDD treatment altered the profile of p27kip1 migration as compared to the LPS-activated control. Time of addition studies demonstrated that the greatest sensitivity of p27kip1 to TCDD treatment occurred within the initial 24 h post-LPS activation. Interestingly, LPS-induced Ig {kappa} light chain and IgM secretion also exhibited the greatest period of sensitivity (i.e., inhibition) to TCDD during the first 24 h post-LPS activation. In addition, TCDD markedly suppressed the LPS-induced differentiation of CH12.LX cells into IgM secreting AFC with a modest but cumulative effect on cell proliferation over a 72 h period. Collectively, these findings show that TCDD altered the cellular concentration and post-translational modification of p27kip1 in this activated B cell cell line model, which occurred concomitantly with altered B cell differentiation and suggests that cyclin-dependent kinase inhibitors may be an important intracellular target in TCDD-mediated inhibition of B cell differentiation.


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B. S. Yoo, D. R. Boverhof, D. Shnaider, R. B. Crawford, T. R. Zacharewski, and N. E. Kaminski
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters the Regulation of Pax5 in Lipopolysaccharide-Activated B Cells
Toxicol. Sci., February 1, 2004; 77(2): 272 - 279.
[Abstract] [Full Text] [PDF]


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