Abstract
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.
Highlights
ASTHMA IS A CHRONIC DISEASE characterized by inflammation and remodeling of the airways
We saw a reduced level of H3K9me3 associated with the CXCL8 promoter in cells isolated from asthmatic individuals compared with those from nonasthmatic individuals (Fig. 1A) and an increased association of H3K4me3 with the CXCL8 promoter in Airway smooth muscle (ASM) cells isolated from asthmatic individuals (Fig. 1B), neither reached statistical significance and they were not investigated further
There was no difference in the levels of histone H4 acetylation at the CXCL8 promoter in cells from asthmatic individuals compared with nonasthmatic individuals (Fig. 1C), histone H3 acetylation at the CXCL8 promoter was increased in cells from asthmatic individuals (Fig. 1D) and we went on to investigate this further
Summary
ASTHMA IS A CHRONIC DISEASE characterized by inflammation and remodeling of the airways. Considered as purely a contractile cell, ASM cells contribute to airway inflammation and remodeling through the production of lipid mediators, chemokines [29], cytokines [47], growth factors [47], matrix metalloproteinases [17], and proangiogenic factors [11]. CXCL8 is a chemokine that mediates its effects via two G protein-coupled receptors, CXCR1 and CXCR2. It is implicated in the pathogenesis of a variety of inflammatory and malignant diseases including inflammatory bowel disease [24], rheumatoid arthritis [22], non-small cell lung cancer [53], and asthma. Inhibitors of BET proteins selectively interfere with gene expression programs that mediate cell growth, apoptosis, and inflammatory responses [14, 15, 40]
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