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ToxSci Advance Access originally published online on July 25, 2003
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Toxicological Sciences 75, 333-342 (2003)
Copyright © 2003 by the Society of Toxicology

IMMUNOTOXICOLOGY

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

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

* Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan 48824, and {dagger} Department of Biology, Kyonggi University, Paldal-gu, Suwon-Si, Korea

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 that is a critical regulator of cellular differentiation. In the well-characterized B-cell line, CH12.LX, a modest decrease in p27kip1was observed during the initial 24-h post-LPS (lipopolysaccharide) activation, which then gradually increased above background at 48 and 72 h. Conversely, in the presence of TCDD, p27kip1was 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 posttranslational modification of p27kip1 in this activated B-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.

Key Words: TCDD; B cell; p27kip1; LPS; cyclin-dependent kinase inhibitor.


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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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