ARYL HYDROCARBON RECEPTOR AND NF-KAPPAB INTERACTIONS

许多研究表明，芳烃受体（AhR）激动剂，包括多环芳烃（PAH），广泛分布在环境中，对免疫系统产生不利影响。 对暴露于AhR激动剂的人群的流行病学分析显示，这些个体存在多方面的免疫功能障碍。 Sherr实验室的研究表明，PAH可快速诱导小鼠骨髓基质细胞依赖性preB细胞凋亡。 前B细胞的“死亡信号”显示由基质细胞通过AhR依赖性机制产生。 初步研究表明，PAH激活骨髓基质细胞中的NF-κ B-DNA结合，并提示NF-κ B也可能参与导致“死亡信号”产生的途径。因此，本研究的具体目的是解决AhR激动剂改变骨髓基质细胞中NF-κ B信号通路的假设，导致不良生物反应，可能包括产生preB细胞死亡信号。“我们将：1）确定骨髓基质细胞中模型PAH/AhR激动剂如何调节NF-κ B，2）确定NF-κ B上游激酶信号级联中PAH介导的改变，和3）确定AhR-p65缔合和转录活性的要求。

Many studies have demonstrated that aryl hydrocarbon receptor (AhR) agonists, including polynuclear aromatic hydrocarbons (PAH) that are ubiquitously distributed in the environment, adversely affect the immune system. Epidemiological analysis of human populations exposed to AhR agonists revealed multi-faceted immune dysfunction in those individuals. Studies in the Sherr laboratory have shown that PAH rapidly induce apoptosis in murine bone marrow stromal cell-dependent preB cells. The preB cell "death signal" was shown to be produced by the stromal cells by an AhR-dependent mechanism. Initial studies have shown that PAH activate NF-kappaB-DNA binding in bone marrow stromal cells and suggested that NF-kappaB also may participate in the pathway leading to production of the "death signal." Therefore, the specific aims of this study were developed to address the hypothesis that AhR agonists alter the NF-kappaB signaling pathway in bone marrow stromal cells, resulting in adverse biological responses potentially including the production of the preB cell "death signal." We will: 1) determine how NF-kappaB is modulated by a model PAH/AhR agonist in bone marrow stromal cells, 2) define PAH-mediated alterations in the kinase signaling cascade upstream of NF-kappaB, and 3) define requirements for AhR-p65 association and transcriptional activity.