Iu Matthew, Zago Michela, Rico de Souza Angela, Bouttier Manuella, Pareek Swati, White John H, Hamid Qutayba, Eidelman David H, Baglole Carolyn J
Department of Medicine, McGill University, Montreal, Quebec, Canada.
Research Institute of the McGill University Health Centre (RI MUHC), Montreal, Quebec, Canada.
Free Radic Biol Med. 2017 Jul;108:19-31. doi: 10.1016/j.freeradbiomed.2017.02.045. Epub 2017 Feb 27.
Chronic obstructive pulmonary disease (COPD) is a chronic and prevalent respiratory disease caused primarily by long term inhalation of cigarette smoke. A major hallmark of COPD is elevated apoptosis of structural lung cells including fibroblasts. The NF-κB member RelB may suppress apoptosis in response to cigarette smoke, but its role in lung cell survival is not known. RelB may act as a pro-survival factor by controlling the expression of superoxide dismutase 2 (SOD2). SOD2 is also regulated by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that suppresses cigarette smoke-induced apoptosis. As the AhR is also a binding partner for RelB, we speculate that RelB suppresses cigarette smoke-induced apoptosis by regulating the AhR. Using an in vitro model of cigarette smoke exposure (cigarette smoke extract [CSE]), we found that CSE down-regulated RelB expression in mouse lung fibroblasts, which was associated with elevated levels of cleaved PARP. Genetic ablation of RelB elevated CSE-induced apoptosis, including chromatin condensation, and reduced mitochondrial function. There was also more reactive oxygen species production in RelB cells exposed to CSE. While there was no alteration in Nrf2 expression or localization between RelB and wild type cells in response to CSE, RelB cells displayed significantly decreased AhR mRNA and protein expression, concomitant with loss of AhR target gene expression (Cyp1a1, Cyp1b1, Nqo1). Finally, we found that RelB binds to the Ahr gene at 3 sites to potentially increase its expression via transcriptional induction. These data support that RelB suppresses cigarette smoke-induced apoptosis, potentially by increasing the AhR. Together, these two proteins may comprise an important cell survival signaling pathway that reduces apoptosis upon cigarette smoke exposure.
慢性阻塞性肺疾病（COPD）是一种主要由长期吸入香烟烟雾引起的慢性常见呼吸道疾病。COPD的一个主要标志是包括成纤维细胞在内的肺结构细胞凋亡增加。NF-κB成员RelB可能会抑制香烟烟雾诱导的细胞凋亡，但其在肺细胞存活中的作用尚不清楚。RelB可能通过控制超氧化物歧化酶2（SOD2）的表达而作为一种促生存因子。SOD2也受芳烃受体（AhR）调节，AhR是一种配体激活的转录因子，可抑制香烟烟雾诱导的细胞凋亡。由于AhR也是RelB的结合伴侣，我们推测RelB通过调节AhR来抑制香烟烟雾诱导的细胞凋亡。使用香烟烟雾暴露的体外模型（香烟烟雾提取物[CSE]），我们发现CSE下调了小鼠肺成纤维细胞中RelB的表达，这与裂解的PARP水平升高有关。RelB的基因敲除增加了CSE诱导的细胞凋亡，包括染色质浓缩，并降低了线粒体功能。暴露于CSE的RelB细胞中也有更多的活性氧产生。虽然在响应CSE时RelB细胞和野生型细胞之间Nrf2的表达或定位没有改变，但RelB细胞显示AhR mRNA和蛋白表达显著降低，同时AhR靶基因表达（Cyp1a1、Cyp1b1、Nqo1）丧失。最后，我们发现RelB在3个位点与Ahr基因结合，可能通过转录诱导增加其表达。这些数据支持RelB可能通过增加AhR来抑制香烟烟雾诱导的细胞凋亡。总之，这两种蛋白可能构成一条重要的细胞存活信号通路，在香烟烟雾暴露时减少细胞凋亡。
