Vogel Christoph F A, Sciullo Eric, Li Wen, Wong Pat, Lazennec Gwendal, Matsumura Fumio
Department of Environmental Toxicology, University of California, Davis, One Shields Avenue, Davis, California 95616, USA.
Mol Endocrinol. 2007 Dec;21(12):2941-55. doi: 10.1210/me.2007-0211. Epub 2007 Sep 6.
The nuclear factor-kappaB (NF-kappaB) transcription factor family has a crucial role in rapid responses to stress and pathogens. We show that the NF-kappaB subunit RelB is functionally associated with the aryl hydrocarbon receptor (AhR) and mediates transcription of chemokines such as IL-8 via activation of AhR and protein kinase A. RelB physically interacts with AhR and binds to an unrecognized RelB/AhR responsive element of the IL-8 promoter linking two signaling pathways to activate gene transcription. We found a time-dependent recruitment of AhR to the RelB/AhR responsive element site of IL-8 mediated by the AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and via activation of protein kinase A. Furthermore, NF-kappaB-binding sites that are preferentially recognized by RelB/p52 are a target for RelB/AhR complexes without addition of any stimuli, implicating the endogenous function of the AhR. RelB/AhR complexes are also found to bind on xenobiotic responsive element, and RelB drastically increases the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced xenobiotic responsive element reporter activity. The interaction of RelB with AhR signaling, and AhR with NF-kappaB RelB signaling pathways represent a new mechanism of cross talk between the two transcription factors.
核因子-κB（NF-κB）转录因子家族在对应激和病原体的快速反应中起关键作用。我们发现NF-κB亚基RelB在功能上与芳烃受体（AhR）相关联，并通过激活AhR和蛋白激酶A介导诸如IL-8等趋化因子的转录。RelB与AhR发生物理相互作用，并结合至IL-8启动子的一个未被识别的RelB/AhR反应元件，从而连接两条信号通路以激活基因转录。我们发现，由AhR配体2,3,7,8-四氯二苯并对二恶英（二恶英）介导并通过蛋白激酶A的激活，AhR会随时间依赖性地募集至IL-8的RelB/AhR反应元件位点。此外，RelB/p52优先识别的NF-κB结合位点是RelB/AhR复合物的作用靶点，无需添加任何刺激，这暗示了AhR的内源性功能。还发现RelB/AhR复合物结合在外源物反应元件上，并且RelB显著增加2,3,7,8-四氯二苯并对二恶英诱导的外源物反应元件报告基因活性。RelB与AhR信号传导以及AhR与NF-κB RelB信号传导途径之间的相互作用代表了这两种转录因子之间相互作用的一种新机制。
