Epigenetic inhibitors differentially impact TGF-β1 signaling cascades in COPD airway smooth muscle cells
File(s)
Published version
Author(s)
Reddy, Karosham Diren
Xenaki, Dikaia
Adcock, Ian M
Oliver, Brian GG
Zakarya, Razia
Type
Journal Article
Abstract
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. Methods: 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. Results: 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. Conclusions: 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.
Date Issued
2025-01-01
Date Acceptance
2024-12-27
Citation
Cells, 2025, 14 (1), pp.31-31
ISSN
2073-4409
Publisher
MDPI AG
Journal / Book Title
Cells
Volume
14
Issue
1
Copyright Statement
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39791732
PII: cells14010031
Subjects
COPD
CXCL8
DNA methylation
TGF-beta
airway smooth muscle
epigenetics
histone acetylation
inflammation
therapeutics
Humans
Pulmonary Disease, Chronic Obstructive
Transforming Growth Factor beta1
DNA Methylation
Myocytes, Smooth Muscle
Epigenesis, Genetic
Signal Transduction
Male
Interleukin-8
Middle Aged
Female
Acetylation
NF-kappa B
Histones
Publication Status
Published
Coverage Spatial
Switzerland
Date Publish Online
2024-12-31