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

Schneider, Dina; Manzan, Maria Alejandra; Yoo, Byung Sun; Crawford, R. J.; Kaminski, Norbert E.

doi:10.1093/toxsci/kfp028

Cited by 28 publications

(42 citation statements)

References 39 publications

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“…A detailed analysis of the first À2000 bp of the Blimp-1 promoter identified two putative DRE sites located within the first À350 bp of the transcriptional start site. Electrophoretic mobility shift assays demonstrated very low TCDD-inducible DNA-binding activity to both of these DRElike sites (Schneider et al, 2009). Taken together, these studies suggest that TCDD does not impair Blimp-1 transcription via direct binding of the AhR to either of the putative DRE sites identified within the Blimp-1 promoter.…”

Section: Effects Of Tcdd On the B-cell Differentiation Programmentioning

confidence: 72%

“…Concordant with TCDD suppressing Blimp-1 induction, impairment of AP-1 DNA-binding activity by TCDD in activated B cells was first reported in LPS-activated CH12.LX cells and was correlated with a decrease in c-jun expression (Suh et al, 2002). A more recent evaluation of three separate TRE within the À2000 bp of the Blimp-1 promoter using nuclear extracts from CH12.LX cells showed induction of AP-1 binding in response to LPS activation, which was markedly impaired in a time-and concentration-dependent manner in the presence of TCDD treatment (Schneider et al, 2009). In addition, the TCDD-mediated inhibition in AP-1-binding activity was sustained up to 72 h post-LPS activation.…”

Section: S181mentioning

confidence: 83%

“…By contrast, a significant decrease in Blimp-1 DNA-binding activity was observed in LPS-activated CH12.LX cells concomitantly treated with TCDD when compared with time-matched controls. The most pronounced effects on Blimp-1 being observed at 24 and 48 h post-LPS activation (Schneider et al, 2009). In addition, Blimp-1 mRNA levels were closely correlated with Blimp-1 DNA-binding activity thus showing strong induction in response to LPS activation in the absence of TCDD and marked impairment in the presence of TCDD.…”

Section: Effects Of Tcdd On the B-cell Differentiation Programmentioning

confidence: 99%

“…Congruently, an assortment of genes, including those encoding cell signaling proteins, cell survival, and apoptotic proteins, cytokines, and transcription factors have been shown to be upregulated or downregulated by TCDD. In addition, DRE-like sites have been identified in the promoter regions of numerous genes some of which have been found to be modulated by AhR activation and some that have yet to be tested (Lai et al, 1996;Schneider et al, 2009). Recently, a combination of whole-genome microarray-based chromatin immunoprecipitation (ChIP-on-chip) and time course gene expression microarray analysis was performed on the mouse B-cell line CH12.LX following exposure to LPS or LPS and TCDD to identify the primary and downstream transcriptional elements of B-cell differentiation that are altered by the AHR (De Abrew et al, 2010).…”

Section: Possible Molecular Targets Involved In B-cell Dysfunction Bymentioning

confidence: 99%

“…Motif analysis of the Pax5 promoter identified 10 putative DRE-like sites within the first À3500-bp region of the transcriptional start site. Unfortunately, experiments assessing whether TCDD treatment induces Pax5 transcription through one or more of these putative DRE-like sites, using a Pax5 promoter reporter for transient transfection assays in CH12.LX cells were not informative due to the expulsion of the reporter plasmid by 24 h (Schneider et al, 2009). Importantly, similar experiments transfecting the Pax5 promoter reporter into Hepa 1c1c7 cells and NIH3T3 cells, which are more amendable to transfection, showed no induction of reporter activity above background after TCDD treatment, suggesting that the activated AhR likely does not directly induce Pax5 transcription.…”

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confidence: 99%

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The Long Winding Road toward Understanding the Molecular Mechanisms for B-Cell Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Sulentic

Kaminski

2010

Toxicological Sciences

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Suppression of humoral immune responses by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was first reported in the mid-1970s. Since this initial observation, much effort has been devoted by many laboratories toward elucidation of the cellular and molecular mechanisms responsible for the profound impairment of humoral immune responses by TCDD, which is characterized by decreased B cell to plasma cell differentiation and suppression of immunoglobulin production. These efforts have led to a significant body of research demonstrating a direct effect of TCDD on B-cell maturation and function as well as a requisite but as yet undefined role of the aryl hydrocarbon receptor (AhR) in these effects. Likewise, a number of molecular targets putatively involved in mediating B-cell dysfunction by TCDD, and other AhR ligands, have been identified. However, our current understanding has primarily relied on findings from mouse models, and the translation of this knowledge to effects on human B cells and humoral immunity in humans is less clear. Therefore, a current challenge is to determine how TCDD and the AhR affect human B cells. Efforts have been made in this direction but continued progress in developing adequate human models is needed. An in-depth discussion of these advances and limitations in elucidating the cellular and molecular mechanisms putatively involved in the suppression of B-cell function by TCDD as well as the implications on human diseases associated in epidemiological studies with exposure to TCDD and dioxin-like compounds is the primary focus of this review.Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; B cell; humoral immunity; immune suppression; AhR.Halogenated aromatic hydrocarbons such as the polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls are persistent environmental toxicants. The most potent of this class of chemicals is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is produced as a by-product during a variety of industrial and municipal processes, many of which involve the combustion of organic materials in the presence of chlorine. TCDD has generated much public concern due to several highly publicized incidents of human and wildlife exposure (reviewed by White and Birnbaum, 2009). Additionally, the sensitivity of rodent models to TCDD-induced toxicity has fueled concern regarding the potential health risks to humans. TCDD produces a broad range of biological effects in animal and cellular models including death, a generalized wasting syndrome, lymphoid involution (especially of the thymus), hepatotoxicity, cardiotoxicity, teratogenicity, developmental toxicity, carcinogenesis, neurotoxicity, immunotoxicity, and various biochemical effects (reviewed by Birnbaum and Tuomisto, 2000).Alterations in immune function, primarily immune suppression, have been observed in virtually every species studied and occurs at doses that do not produce obvious signs of toxicity in vivo and at noncytotoxic concentrations in vitro (Holsapple et al., 1991b;Kerkvliet, 2002). These alterations include ...

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Section: Effects Of Tcdd On the B-cell Differentiation Programmentioning

confidence: 72%

Section: S181mentioning

confidence: 83%

Section: Effects Of Tcdd On the B-cell Differentiation Programmentioning

confidence: 99%

Section: Possible Molecular Targets Involved In B-cell Dysfunction Bymentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

The Long Winding Road toward Understanding the Molecular Mechanisms for B-Cell Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Sulentic

Kaminski

2010

Toxicological Sciences

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TCDD, AHR, and Immune Regulation

Kerkvliet

2011

The AH Receptor in Biology and Toxicology

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The role of the aryl hydrocarbon receptor in normal and malignant B cell development

Sherr

Monti

2013

Semin Immunopathol

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically studied for its role in environmental chemical-mediated toxicity and carcinogenicity. In the last 5 years, however, it has become clear that the AhR, presumably activated by endogenous ligand(s), plays an important role in immune system development and function. Other articles in this edition summarize AhR function during T cell and antigen-presenting cell development and function, including the effects of AhR activation on dendritic cell function, T cell skewing, inflammation, and autoimmune disease. Here, we focus on AhR expression and function during B cell differentiation. Studies exploiting immunosuppressive environmental chemicals to probe the role of the AhR in humoral immunity are also reviewed to illustrate the multiple levels at which a “nominally activated” AhR could control B cell differentiation from the hematopoietic stem cell through the pro-B cell, mature B cell, and antibody-secreting plasma cell stages. Finally, a putative role for the AhR in the basic biology of B cell malignancies, many of which have been associated with exposure to environmental AhR ligands, is discussed.

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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

Cited by 28 publications

References 39 publications

The Long Winding Road toward Understanding the Molecular Mechanisms for B-Cell Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

The Long Winding Road toward Understanding the Molecular Mechanisms for B-Cell Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

TCDD, AHR, and Immune Regulation

The role of the aryl hydrocarbon receptor in normal and malignant B cell development

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