ToxSci Advance Access published online on February 23, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp028
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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
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* Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA
Department of Biology, Kyonggi University, Paldal-gu, Suwon-Si, Korea
# Authors have equally contributed to this publication and share first authorship
To whom correspondence should be addressed: Dr. Norbert E. Kaminski, Department of Pharmacology and Toxicology, 315 Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824, Phone: 517-355-3786, Fax: 517-432-3218 E-mail: kamins11{at}msu.edu
Received October 7, 2008; revision received February 6, 2009; accepted February 6, 2009
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Abstract |
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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 (AHR). 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 IgM 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 mRNA and DNA-binding activity within the Pax5 promoter were suppressed by TCDD. Furthermore, LPS-activation of CH12.LX cells up-regulated DNA-binding activity of activator protein 1 (AP-1) at three TRE-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.
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