ToxSci Advance Access originally published online on February 23, 2009
Toxicological Sciences 2009 108(2):377-388; doi:10.1093/toxsci/kfp028
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
,1,1
,2
* Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824
Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824
Department of Biology, Kyonggi University, Paldal-gu, Suwon-Si, Korea
2 To whom correspondence should be addressed: Department of Pharmacology and Toxicology, 315 Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824. Fax: (517) 432-3218. E-mail: kamins11{at}msu.edu.
Received October 7, 2008; accepted February 6, 2009
 |
Abstract |
|---|
B cell differentiation and humoral immune responses are markedly suppressed by the persistent environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The suppression of humoral immune responses by TCDD occurs by direct actions on the B cell and involves activation of the aryl hydrocarbon receptor. Transcriptional regulation of paired box gene 5 (Pax5), an important regulator of B cell differentiation, is altered by TCDD in concordance with the suppression of B cell differentiation and humoral immunoglobulin M response. We hypothesized that TCDD treatment leads to dysregulation of Pax5 transcription by interfering with the basic B cell differentiation mechanisms and aimed to determine the effects of TCDD on upstream regulators of Pax5. A critical regulator of B cell differentiation, B lymphocyte–induced maturation protein-1 (Blimp-1) acts as a transcriptional repressor of Pax5. In lipopolysaccharide (LPS)-activated murine B cell lymphoma, CH12.LX, Blimp-1 messenger RNA, and DNA-binding activity within the Pax5 promoter were suppressed by TCDD. Furthermore, LPS activation of CH12.LX cells upregulated DNA-binding activity of activator protein 1 (AP-1) at three responsive element–like motifs within the Blimp-1 promoter. TCDD treatment of LPS-activated CH12.LX cells suppressed AP-1 binding to these motifs between 24 and 72 h, in concordance with the suppression of Blimp-1 by TCDD. A more comprehensive analysis at 72 h demonstrated that the suppression of AP-1 binding within the Blimp-1 promoter by TCDD was concentration dependent. In summary, our findings link the TCDD-mediated suppression of Blimp-1 through AP-1 to the dysregulation of Pax5, which ultimately leads to the suppression of B cell differentiation and humoral immune responses.
Key Words: TCDD; LPS; B cell; Pax5; Blimp-1; AP-1.
1 Authors have equally contributed to this publication and share first authorship.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. M. North, R. B. Crawford, H. Lu, and N. E. Kaminski Simultaneous In Vivo Time Course and Dose Response Evaluation for TCDD-Induced Impairment of the LPS-stimulated Primary IgM Response Toxicol. Sci., November 1, 2009; 112(1): 123 - 132. [Abstract] [Full Text] [PDF]
|
|