Constitutive activation and environmental chemical induction of the aryl hydrocarbon receptor/transcription factor in activated human B lymphocytes
Constitutive activation and environmental chemical induction of the aryl hydrocarbon receptor/transcription factor in activated human B lymphocytes
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DOI：
10.1124/mol.104.009100
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发表时间：
2005-05-01
影响因子：
3.6
通讯作者：
Sherr, DH
中科院分区：
文献类型：
--
作者：
Allan, LL;Sherr, DH
芳烃受体（AhR）是一种配体激活的转录因子，介导由多种普遍存在的环境污染物（包括多环芳烃、多氯联苯和二恶英）引起的免疫抑制。尽管在没有环境化学物质的情况下 AhR 的正常生理作用尚不确定，但最近的研究表明它对细胞生长和凋亡的贡献。由于在动物模型中 B 细胞似乎直接受到 AhR 配体的影响，因此推测 AhR 主要在活化的人类 B 细胞中表达，并且它可能有助于细胞生长调节。为了开始解决这些问题并将 AhR 功能的详细分析扩展到人类系统，研究了静息和激活的人类 B 细胞中的 AhR 表达。此外，还研究了激活的 B 细胞对环境 AhR 配体的反应，以深入了解 AhR 可能的生理作用。静息外周人类 B 细胞很少或不表达 AhR。然而，用 CpG 或 CD40 配体激活会显着上调 AhR mRNA 和蛋白质。在没有外源配体的情况下，受刺激的 B 细胞中，AhR 核易位、组成型 DNA 结合以及 AhR 调节基因 CYP1A1 的诱导表明了 AhR 的组成型激活。 AhR 上调不需要细胞分裂。用原型环境 AhR 配体苯并[a]芘处理表达 AhR 的 B 细胞，可显着抑制细胞生长。这些数据有助于解释 B 细胞对环境 AhR 配体的敏感性，并强烈表明 AhR 在人类 B 细胞区室中发挥重要功能。
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates immunosuppression induced by a variety of ubiquitous environmental pollutants, including polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and dioxins. Although the normal physiological role for the AhR in the absence of environmental chemicals is uncertain, recent studies suggest its contribution to cell growth and apoptosis. Because B cells seem to be directly affected by AhR ligands in animal models, it was postulated that the AhR is predominantly expressed in activated human B cells and that it may contribute to cell growth regulation. To begin to address these issues and to extend detailed analyses of AhR function to a human system, AhR expression in resting and activated human B cells was studied. In addition, the response of activated B cells to an environmental AhR ligand was investigated to provide insight into a possible physiological role for the AhR. Resting peripheral human B cells expressed little or no AhR. However, activation with CpG or CD40 ligand profoundly up-regulated AhR mRNA and protein. AhR nuclear translocation, constitutive DNA binding, and induction of an AhR-regulated gene, CYP1A1, in stimulated B cells in the absence of exogenous ligands suggested constitutive AhR activation. Cell division was not required for AhR up-regulation. Treatment of AhR- expressing B cells with a prototypic environmental AhR ligand, benzo[a] pyrene, significantly suppressed cell growth. These data help explain the sensitivity of B cells to environmental AhR ligands and strongly suggest that the AhR plays an important function within the human B cell compartment.