Reddy Karosham Diren, Xenaki Dikaia, Adcock Ian M, Oliver Brian G G, Zakarya Razia
Respiratory Cellular and Molecular Biology Group, Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, Sydney, NSW 2113, Australia.
School of Life Science, University of Technology Sydney, Ultimo, NSW 2007, Australia.
Cells. 2024 Dec 31;14(1):31. doi: 10.3390/cells14010031.
Chronic obstructive pulmonary disease (COPD) is characterized by progressive and incurable airflow obstruction and chronic inflammation. Both TGF-β1 and CXCL8 have been well described as fundamental to COPD progression. DNA methylation and histone acetylation, which are well-understood epigenetic mechanisms regulating gene expression, are associated with COPD progression. However, a deeper understanding of the complex mechanisms associated with DNA methylation, histone post-translational changes and RNA methylation in the context of regulatory pathways remains to be elucidated. We here report on how DNA methylation and histone acetylation inhibition differentially affect CXCL8 signaling in primary human non-COPD and COPD airway cells. Airway smooth muscle (ASM) cells, a pivotal cell type in COPD, were isolated from the small airways of heavy smokers with and without COPD. Histone acetylation and DNA methylation were inhibited before the TGF-β1 stimulation of cells. Subsequently, CXCL8 production and the abundance and activation of pertinent transcription regulatory proteins (NF-κB, p38 MAPK and JNK) were analyzed. TGF-β1-stimulated CXCL8 release from ASM cells from 'healthy' smoker subjects was significantly modulated by DNA methylation (56.32 pg/mL and 56.60 pg/mL) and acetylation inhibitors (27.50 pg/mL and 48.85 pg/mL) at 24 and 48 h, respectively. However, modulation via the inhibition of DNA methylation (34.06 pg/mL and 43.18 pg/mL) and acetylation (23.14 pg/mL and 27.18 pg/mL) was observed to a lesser extent in COPD ASM cells. These changes were associated with differences in the TGF-β1 activation of NF-κB and MAPK pathways at 10 and 20 min. Our findings offer insight into differential epigenetics in controlling COPD ASM cells and provide a foundation warranting future studies on epigenetic differences associated with COPD diagnosis. This would provide a scope for developing therapeutic interventions targeting signaling and epigenetic pathways to improve patient outcomes.
慢性阻塞性肺疾病（COPD）的特征是进行性且无法治愈的气流阻塞和慢性炎症。转化生长因子-β1（TGF-β1）和趋化因子配体8（CXCL8）均被充分描述为COPD进展的关键因素。DNA甲基化和组蛋白乙酰化是调节基因表达的表观遗传机制，与COPD进展相关。然而，在调控途径的背景下，对与DNA甲基化、组蛋白翻译后修饰和RNA甲基化相关的复杂机制仍有待深入了解。我们在此报告DNA甲基化和组蛋白乙酰化抑制如何在原代人非COPD和COPD气道细胞中差异影响CXCL8信号传导。气道平滑肌（ASM）细胞是COPD中的关键细胞类型，从有和没有COPD的重度吸烟者的小气道中分离出来。在细胞受到TGF-β1刺激之前，抑制组蛋白乙酰化和DNA甲基化。随后，分析CXCL8的产生以及相关转录调节蛋白（核因子κB（NF-κB）、p38丝裂原活化蛋白激酶（p38 MAPK）和c-Jun氨基末端激酶（JNK））的丰度和激活情况。在24小时和48小时时，DNA甲基化（分别为56.32 pg/mL和56.60 pg/mL）和乙酰化抑制剂（分别为27.50 pg/mL和48.85 pg/mL）对来自“健康”吸烟者受试者的ASM细胞经TGF-β1刺激后的CXCL8释放有显著调节作用。然而，在COPD ASM细胞中，通过抑制DNA甲基化（34.06 pg/mL和43.18 pg/mL）和乙酰化（23.14 pg/mL和27.18 pg/mL）的调节作用较小。这些变化与10分钟和20分钟时TGF-β1对NF-κB和丝裂原活化蛋白激酶（MAPK）途径的激活差异有关。我们的研究结果为控制COPD ASM细胞中的差异表观遗传学提供了见解，并为未来关于与COPD诊断相关的表观遗传差异的研究提供了基础。这将为开发针对信号传导和表观遗传途径的治疗干预措施以改善患者预后提供空间。
