Sundar Isaac K, Rashid Kahkashan, Sellix Michael T, Rahman Irfan
Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA.
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester Medical Center, Rochester, NY, USA.
Biochem Biophys Res Commun. 2017 Dec 2;493(4):1390-1395. doi: 10.1016/j.bbrc.2017.09.157. Epub 2017 Sep 30.
REV-ERBα is a nuclear heme receptor, transcriptional repressor and critical component of the molecular clock that drives daily rhythms of metabolism. Evidence reveals that REV-ERBα also plays an important regulatory role in clock-dependent lung physiology and inflammatory responses. We hypothesize that cigarette smoke (CS) exposure influences REV-ERBα abundance in the lungs, facilitating a pro-inflammatory phenotype. To determine the impact of REV-ERBα activation in the CS-induced inflammatory response we treated primary human small airway epithelial cells (SAECs) with CS extract (CSE) or lipopolysaccharide (LPS) in the absence or presence of pre-treatment with the REV-ERBα agonist GSK 4112. We also exposed adult C57BL/6J (WT) and Rev-erbα global KO mice to CS (10 and 30 days) and measured pro-inflammatory cytokine release. Our data reveal that pre-treatment with GSK 4112 reduced CSE/LPS induced pro-inflammatory cytokines release from both SAECs and mouse lung fibroblasts (MLFs). Furthermore, REV-ERBα KO mice show a greater inflammatory response to 10 and 30 days of CS, including increased neutrophil lung influx, pro-inflammatory cytokine (IL-6, MCP-1 and KC) release, and pro-senescence marker (p16) when compared to WT mice. These data demonstrate that REV-ERBα is a critical regulator of CS-induced lung inflammatory responses.
REV-ERBα是一种核血红素受体、转录抑制因子，也是驱动每日代谢节律的分子时钟的关键组成部分。有证据表明，REV-ERBα在依赖时钟的肺生理和炎症反应中也发挥着重要的调节作用。我们假设，接触香烟烟雾（CS）会影响肺中REV-ERBα的丰度，促进促炎表型的形成。为了确定REV-ERBα激活对CS诱导的炎症反应的影响，我们在存在或不存在REV-ERBα激动剂GSK 4112预处理的情况下，用CS提取物（CSE）或脂多糖（LPS）处理原代人小气道上皮细胞（SAECs）。我们还将成年C57BL/6J（野生型，WT）和Rev-erbα基因敲除（KO）小鼠暴露于CS中（10天和30天），并测量促炎细胞因子的释放。我们的数据显示，用GSK 4112预处理可减少CSE/LPS诱导的SAECs和小鼠肺成纤维细胞（MLFs）促炎细胞因子的释放。此外，与WT小鼠相比，REV-ERBα基因敲除小鼠对10天和30天的CS表现出更大的炎症反应，包括中性粒细胞肺内流增加、促炎细胞因子（IL-6、MCP-1和KC）释放以及衰老前标志物（p16）增加。这些数据表明，REV-ERBα是CS诱导的肺部炎症反应的关键调节因子。
