CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: regulation by BET

被引：50
作者：
Clifford, Rachel L. [1 ,2 ]
Patel, Jamie K. [1 ,2 ]
John, Alison E. [1 ,2 ]
Tatler, Amanda L. [1 ,2 ]
Mazengarb, Lisa [1 ,2 ]
Brightling, Christopher E. [3 ]
Knox, Alan J. [1 ,2 ]
机构：
[1] Univ Nottingham, Dept Resp Med, Nottingham NG7 2RD, England
[2] Univ Nottingham, Nottingham Resp Res Unit, Nottingham NG7 2RD, England
[3] Univ Leicester, Inst Lung Hlth, Dept Infect Immun & Inflammat, Leicester, Leics, England
来源：
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY | 2015年 / 308卷 / 09期
基金：
英国惠康基金; 英国国家替代、减少和改良动物研究中心;
关键词：
airway smooth muscle; asthma; histone acetylation; bromodomain; BET protein; CXCl8; GROWTH-FACTOR; BROMODOMAIN INHIBITION; SELECTIVE-INHIBITION; HEART-FAILURE; C-MYC; CELLS; EXPRESSION; METHYLATION; PATTERNS; IL-8;
D O I：
10.1152/ajplung.00021.2015
中图分类号：
Q4 [生理学];
学科分类号：
071003 ;
摘要：
Asthma is characterized by airway inflammation and remodeling and CXCL8 is a CXC chemokine that drives steroid-resistant neutrophilic airway inflammation. We have shown that airway smooth muscle (ASM) cells isolated from asthmatic individuals secrete more CXCL8 than cells from nonasthmatic individuals. Here we investigated chromatin modifications at the CXCL8 promoter in ASM cells from nonasthmatic and asthmatic donors to further understand how CXCL8 is dysregulated in asthma. ASM cells from asthmatic donors had increased histone H3 acetylation, specifically histone H3K18 acetylation, and increased binding of histone acetyltransferase p300 compared with nonasthmatic donors but no differences in CXCL8 DNA methylation. The acetylation reader proteins Brd3 and Brd4 were bound to the CXCL8 promoter and Brd inhibitors inhibited CXCL8 secretion from ASM cells by disrupting Brd4 and RNA polymerase II binding to the CXCL8 promoter. Our results show a novel dysregulation of CXCL8 transcriptional regulation in asthma characterized by a promoter complex that is abnormal in ASM cells isolated from asthmatic donors and can be modulated by Brd inhibitors. Brd inhibitors may provide a new therapeutic strategy for steroid-resistant inflammation.
引用
收藏
页码：L962 / L972
页数：11
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