Epigenetic Inhibitors Differentially Impact TGF-β1 Signaling Cascades in COPD Airway Smooth Muscle Cells
<b>Background:</b> 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 ar...
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MDPI AG
2024-12-01
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| author | Karosham Diren Reddy Dikaia Xenaki Ian M. Adcock Brian G. G. Oliver Razia Zakarya |
| author_facet | Karosham Diren Reddy Dikaia Xenaki Ian M. Adcock Brian G. G. Oliver Razia Zakarya |
| author_sort | Karosham Diren Reddy |
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| description | <b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> 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. |
| format | Article |
| id | doaj-art-00394a60e5de43e59296708b4947bc2e |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-00394a60e5de43e59296708b4947bc2e2025-01-10T13:16:18ZengMDPI AGCells2073-44092024-12-011413110.3390/cells14010031Epigenetic Inhibitors Differentially Impact TGF-β1 Signaling Cascades in COPD Airway Smooth Muscle CellsKarosham Diren Reddy0Dikaia Xenaki1Ian M. Adcock2Brian G. G. Oliver3Razia Zakarya4Respiratory Cellular and Molecular Biology Group, Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, Sydney, NSW 2113, AustraliaRespiratory Cellular and Molecular Biology Group, Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, Sydney, NSW 2113, AustraliaAirways Disease, Respiratory Cell & Molecular Biology, Airways Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2BX, UKRespiratory Cellular and Molecular Biology Group, Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, Sydney, NSW 2113, AustraliaSchool of Life Science, University of Technology Sydney, Ultimo, NSW 2007, Australia<b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> 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.https://www.mdpi.com/2073-4409/14/1/31COPDepigeneticsairway smooth muscleinflammationDNA methylationhistone acetylation |
| spellingShingle | Karosham Diren Reddy Dikaia Xenaki Ian M. Adcock Brian G. G. Oliver Razia Zakarya Epigenetic Inhibitors Differentially Impact TGF-β1 Signaling Cascades in COPD Airway Smooth Muscle Cells Cells COPD epigenetics airway smooth muscle inflammation DNA methylation histone acetylation |
| title | Epigenetic Inhibitors Differentially Impact TGF-β1 Signaling Cascades in COPD Airway Smooth Muscle Cells |
| title_full | Epigenetic Inhibitors Differentially Impact TGF-β1 Signaling Cascades in COPD Airway Smooth Muscle Cells |
| title_fullStr | Epigenetic Inhibitors Differentially Impact TGF-β1 Signaling Cascades in COPD Airway Smooth Muscle Cells |
| title_full_unstemmed | Epigenetic Inhibitors Differentially Impact TGF-β1 Signaling Cascades in COPD Airway Smooth Muscle Cells |
| title_short | Epigenetic Inhibitors Differentially Impact TGF-β1 Signaling Cascades in COPD Airway Smooth Muscle Cells |
| title_sort | epigenetic inhibitors differentially impact tgf β1 signaling cascades in copd airway smooth muscle cells |
| topic | COPD epigenetics airway smooth muscle inflammation DNA methylation histone acetylation |
| url | https://www.mdpi.com/2073-4409/14/1/31 |
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