Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis.
Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis.
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DOI：
10.4049/jimmunol.1700289
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发表时间：
2017-11-15
期刊：
影响因子：
--
通讯作者：
Kaminski NE
中科院分区：
文献类型：
--
作者：
Li J;Bhattacharya S;Zhou J;Phadnis-Moghe AS;Crawford RB;Kaminski NE
芳烃受体（AHR）是一种配体激活的转录因子，介导对内源性和环境化学信号的生物反应。越来越多的证据表明，AHR在调节免疫系统中多种细胞谱系的发育、稳态和功能方面发挥生理作用。然而，AHR在人B细胞发育中的作用尚未研究。为此，使用人脐带血CD 34+造血干/祖细胞（HSPC），采用体外无饲养层的人B细胞发育模型系统。使用该模型，我们发现高亲和力配体2，3，7，8-四氯二苯并-p-二恶英（TCDD）激活AHR显著抑制HSPCs的早期B细胞和前B细胞的产生，表明B细胞谱系特化和定型受损。添加AHR拮抗剂逆转TCDD引起的早期B和前B细胞的抑制，表明AHR在调节B淋巴细胞生成中的作用。基因表达分析显示EBF 1和PAX 5的mRNA水平显著降低，这两个关键的转录因子指导B细胞谱系特化和定型。此外，结合的配体激活AHR的推定的二恶英响应元件在EBF 1启动子被证明通过电泳迁移率变动分析和染色质免疫沉淀分析，这表明转录调控EBF 1 AHR。综上所述，本研究证明了AHR在调节人类B细胞发育中的作用，并表明AHR对EBF 1的转录改变参与了潜在的机制。
Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates biological responses to endogenous and environmental chemical cues. Increasing evidence shows that the AHR plays physiological roles in regulating development, homeostasis and function of a variety of cell lineages in the immune system. However, the role of AHR in human B cell development has not been investigated. Toward this end, an in vitro feeder-free human B cell developmental model system was employed using human cord blood CD34+ hematopoietic stem/progenitor cells (HSPC). Using this model, we found that AHR activation by the high affinity ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), significantly suppressed the generation of early-B cells and pro-B cells from HSPCs, indicating the impairment of B cell lineage specification and commitment. Addition of an AHR antagonist reversed TCDD-elicited suppression of early-B and pro-B cells, suggesting a role of AHR in regulating B lymphopoiesis. Gene expression analysis revealed a significant decrease in the mRNA level of EBF1 and PAX5, two critical transcription factors directing B cell lineage specification and commitment. In addition, binding of the ligand-activated AHR to the putative dioxin response elements in the EBF1 promoter was demonstrated by electrophoretic mobility shift assays and chromatin immunoprecipitation analysis, suggesting transcriptional regulation of EBF1 by AHR. Taken together, this study demonstrates a role for the AHR in regulating human B cell development, and suggests that transcriptional alterations of EBF1 by the AHR are involved in the underlying mechanism.
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E2A蛋白促进淋巴酸化的多能祖细胞的发展。
影响因子：
32.4
作者：
Dias, Sheila;Mansson, Robert;Gurbuxani, Sandeep;Sigvardsson, Mikael;Kee, Barbara L.
通讯作者：
Kee, Barbara L.
影响因子：
64.8
作者：
Mullighan, Charles G.;Goorha, Salil;Downing, James R.
通讯作者：
Downing, James R.
影响因子：
2.3
作者：
Becher, H;FleschJanys, D;Wahrendorf, J
通讯作者：
Wahrendorf, J
DOI：
10.1002/0471140856.tx0408s11
发表时间：
2002-05-01
期刊：
Current protocols in toxicology
影响因子：
--
作者：
Denison, Michael S;Rogers, Jane M;Heath-Pagliuso, Sharon
通讯作者：
Heath-Pagliuso, Sharon
影响因子：
5.4
作者：
Floret, N;Mauny, F;Viel, JF
通讯作者：
Viel, JF