2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters the Regulation of Pax5 in Lipopolysaccharide-Activated B Cells

Yoo, Byung Sun; Boverhof, Darrell R.; Shnaider, Dina; Crawford, R. J.; Zacharewski, Timothy R.; Kaminski, Norbert E.

doi:10.1093/toxsci/kfh013

Cited by 29 publications

(44 citation statements)

References 30 publications

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“…ITE may mainly affect B cell differentiation into Igsecreting plasma cells by suppressing the expression of XBP-1 at the transcriptional level, but its precise mode of action remains elusive. Some papers have reported that TCDD treatment impaired the downregulation of Pax5, which is a repressor of B cell differentiation and a transcriptional repressor of XBP-1 (21,24). In contrast, we observed that there was no change in the expression of Pax-5 mRNA in ITE-treated mouse B cells.…”

Section: Effects Of Ahr Ligands On Plasma Cell Differentiation Of Moucontrasting

confidence: 82%

Effects of AhR ligands on the production of immunoglobulins in purified mouse B cells

et al. 2012

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The aryl hydrocarbon receptor (AhR) has been shown to play important roles in the immune system, and contributions of AhR ligands to the differentiation and functions of Th17/Treg cells have recently been established. However, it has not been fully clarified whether AhR plays roles in B cell differentiation and functions. The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly potent AhR agonist, was reported to suppress the production of immunoglobulin M (IgM) in a transformed mouse B cell line. However, TCDD exhibits high toxicity toward cells and has unknown activities except for its action as an AhR agonist. In the present study, we tried to clarify how an endogenously generated AhR agonist affects mouse B cell differentiation and functions in terms of the direct effects on the expression of Ig subclasses in purified mouse B cells stimulated with an anti-CD40 antibody and interleukin-4. The AhR agonist 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), which is derived via tryptophan metabolism, suppressed the expression of not only IgM, but also IgG1 and IgE. ITE was also found to suppress the expression of secreted-type Ig mRNAs and plasma cell-specific genes. These findings indicate that the endogenous AhR agonist suppresses B cell differentiation into Ig-secreting plasma cells.

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Section: Effects Of Ahr Ligands On Plasma Cell Differentiation Of Moucontrasting

confidence: 82%

Effects of AhR ligands on the production of immunoglobulins in purified mouse B cells

et al. 2012

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“…However, little is known about the mechanism by which TCDD-mediated suppression of B cell differentiation occurs and what other aspects of B cell differentiation, besides the IgM response, are affected by TCDD treatment. In previous studies, TCDD treatment of LPS-activated CH12.LX cells was shown to markedly reduce the mRNA levels of IgH, Ig, and IgJ as well as protein levels of XBP-1 (Yoo et al, 2004). In activated B cells treated with TCDD, Pax5 mRNA and protein levels remained abnormally elevated, and they also maintained abnormally high DNA binding activity as identified in nuclear extracts (Yoo et al, 2004).…”

Section: Introductionmentioning

confidence: 90%

“…In previous studies, TCDD treatment of LPS-activated CH12.LX cells was shown to markedly reduce the mRNA levels of IgH, Ig, and IgJ as well as protein levels of XBP-1 (Yoo et al, 2004). In activated B cells treated with TCDD, Pax5 mRNA and protein levels remained abnormally elevated, and they also maintained abnormally high DNA binding activity as identified in nuclear extracts (Yoo et al, 2004). In addition to transcriptional regulation, the expression of Pax5 can be modulated by mechanisms involving post-transcriptional modifications (Zwollo et al, 1997;Lin et al, 2002).…”

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confidence: 89%

2,3,7,8-Tetrachlorodibenzo-p-dioxin-Mediated Impairment of B Cell Differentiation Involves Dysregulation of Paired Box 5 (Pax5) Isoform, Pax5a

Schneider¹,

Manzan²,

Crawford³

et al. 2008

J Pharmacol Exp Ther

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The persistent environmental contaminant and immunotoxicant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), markedly suppresses humoral immune responses. We recently reported impaired down-regulation of paired box 5 (Pax5), a repressor of B cell differentiation and concomitant suppression of the IgM response by TCDD in the murine CH12.LX B cell line. The objectives of the current study were to determine the impact of TCDD treatment on molecular outcomes characteristic of terminal B cell differentiation and to assess the role that Pax5 isoforms plays in the suppression of B cell differentiation by TCDD. In this study, we show that the highly abundant fulllength Pax5 isoform, Pax5a, and at least two additional modestly expressed Pax5 isoforms were expressed in CH12.LX and splenic B cells. In lipopolysaccharide (LPS)-activated B cells, all of the identified Pax5 isoforms were synchronously down-regulated, and in the presence of TCDD cotreatment they were abnormally and synchronously elevated, suggesting a common mechanism of regulation. Furthermore, B cell differentiation markers X-box protein-1 and major histocompatibility complex class II showed that the levels to which Pax5 was derepressed by TCDD were sufficient to impair B cell differentiation and immunoglobulin gene expression. Confirming the involvement of Pax5, ectopic expression of Pax5a in the LPS-activated CH12.LX cells closely mimicked the suppression of the IgM response by TCDD. In summary, our results demonstrate that Pax5a has a critical role in both the TCDD-mediated impairment of B cell differentiation and the suppression of the humoral immune response.Suppression of primary humoral immune responses is one of the most sensitive sequela associated with exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ubiquitous environmental contaminant. This suppression is characterized by a striking reduction in plasma cell formation and IgM secretion, and it is mediated through a direct effect by TCDD on B cells (Holsapple et al., 1986;Sulentic et al., 1998). TCDD serves as a ligand for the basic-helix-loop-helix/periodicity/ aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT)/simple-minded family protein, AHR (Hankinson, 1995). Previous studies in mice and B cell lines that differ in AHR expression demonstrated the involvement of AHR in the suppression of humoral immune responses (Vecchi et al., 1983;Kerkvliet et al., 1990;Sulentic et al., 1998;Sulentic et al., 2000). The AHR is a 95 to 110-kDa cytoplasmic receptor (Burbach et al., 1992) that exists as part of a multimeric complex composed of dimers of heat shock protein 90 and the AHR-interactive protein (Bell and Poland, 2000;Petrulis and Perdew, 2002). Binding of TCDD to the AHR results in both the dissociation of AHR from the cytosolic complex and the nuclear translocation of the receptor where it releases heat shock protein 90 subunits and undergoes dimerization with ARNT (Whitelaw et al., 1995;Rowlands and Gustafsson, 1997). The interaction of the AHR/ARNT dimers with dioxinresponse e...

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“…Removal of protein binding to the DRE and B sites may alter DNA binding or protein-protein interactions of transcription factors with affinity for these flanking DNA motifs. Additionally, TCDD has been shown to alter the regulation and expression of Pax5/BSAP in LPS-stimulated CH12.LX cells (Yoo et al, 2004). Specifically, TCDD maintains the expression of BSAP, which is typically down-regulated during B cell differentiation into plasma cells.…”

Section: Downloaded Frommentioning

confidence: 99%

2,3,7,8-Tetrachlorodibenzo-p-dioxin, an Exogenous Modulator of the 3′α Immunoglobulin Heavy Chain Enhancer in the CH12.LX Mouse Cell Line

Sulentic¹,

Zhang²,

Na³

et al. 2004

J Pharmacol Exp Ther

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Transcriptional regulation of the Ig heavy chain gene involves several regulatory elements, including the 3Ј␣ enhancer, which is composed of four distinct regulatory domains. DNA binding sites for several transcription factors, including B cell-specific activator protein, nuclear factor for immunoglobulin chain in B cells, and octamer have been identified within the 3Ј␣ enhancer domains and are believed to be important in regulating 3Ј␣ enhancer activity. We have identified an additional DNA binding motif, the dioxin-responsive element (DRE), which can contribute to 3Ј␣ enhancer regulation. 2,3,7,8-Tetrachlorodibenzo-pdioxin (TCDD), a known disrupter of B cell differentiation (i.e., decreased plasma cell formation, inhibition of heavy chain expression, and suppression of IgM secretion), induces binding of the aryl hydrocarbon receptor (AhR) nuclear complex to DREs. TCDD also induces AhR binding to the hypersensitive (hs)4 domain of the 3Ј␣ enhancer. Interestingly, TCDD enhances LPS-induced activation of the hs4 domain but profoundly inhibits LPS-induced activation of the complete 3Ј␣ enhancer. Furthermore, site-directed mutational analysis demonstrated that a DRE and B element in the hs4 domain is modulated by TCDD in lipopolysaccharide-activated B cells. We propose that the AhR is a novel transcriptional regulator of the 3Ј␣ enhancer, which can mediate, at least in part, the effects of TCDD on the 3Ј␣ enhancer and its domains, putatively contributing to a marked suppression of IgM production.Regulation of the murine immunoglobulin heavy chain (IgH) locus is governed through a complex interaction of several regulatory elements whose activity is B cell-specific and dependent on the state of B cell maturation. The most 5Ј regulatory element is the V H promoter, which lies immediately upstream of each variable region and contributes to B cell-specific activity of the Ig heavy chain locus. Located between the rearranged VDJ segments and the C constant region is the E, which contributes to B cell-specific activity and is involved early in B cell development where it regulates

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters the Regulation of Pax5 in Lipopolysaccharide-Activated B Cells

Cited by 29 publications

References 30 publications

Effects of AhR ligands on the production of immunoglobulins in purified mouse B cells

Effects of AhR ligands on the production of immunoglobulins in purified mouse B cells

2,3,7,8-Tetrachlorodibenzo-p-dioxin-Mediated Impairment of B Cell Differentiation Involves Dysregulation of Paired Box 5 (Pax5) Isoform, Pax5a

2,3,7,8-Tetrachlorodibenzo-p-dioxin, an Exogenous Modulator of the 3′α Immunoglobulin Heavy Chain Enhancer in the CH12.LX Mouse Cell Line

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