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Epigenetic dysregulation of interleukin 8 (CXCL8) hypersecretion in cystic fibrosis airway epithelial cells

Poghosyan, Anna; Patel, Jamie K.; Clifford, Rachel L.; Knox, Alan J.

Authors

Anna Poghosyan

Jamie K. Patel

Rachel L. Clifford

Alan J. Knox



Abstract

Airway epithelial cells in cystic fibrosis (CF) overexpress Interleukin 8 (CXCL8) through poorly defined mechanisms. CXCL8 transcription is dependent on coordinated binding of CCAAT/enhancer binding protein (C/EBP)β, nuclear factor (NF)-κB, and activator protein (AP)-1 to the promoter. Here we show abnormal epigenetic regulation is responsible for CXCL8 overexpression in CF cells. Under basal conditions CF cells had increased bromodomain (Brd)3 and Brd4 recruitment and enhanced NF-κB and C/EBPβ binding to the CXCL8 promoter compared to non-CF cells due to trimethylation of histone H3 at lysine 4 (H3K4me3) and DNA hypomethylation at CpG6. IL-1β increased NF-κB, C/EBPβ and Brd4 binding. Furthermore, inhibitors of bromodomain and extra-terminal domain family (BET) proteins reduced CXCL8 production in CF cells suggesting a therapeutic target for the BET pathway.

Citation

Poghosyan, A., Patel, J. K., Clifford, R. L., & Knox, A. J. (2016). Epigenetic dysregulation of interleukin 8 (CXCL8) hypersecretion in cystic fibrosis airway epithelial cells. Biochemical and Biophysical Research Communications, 476(4), 431-437. https://doi.org/10.1016/j.bbrc.2016.05.140

Journal Article Type Article
Acceptance Date May 26, 2016
Publication Date Aug 5, 2016
Deposit Date Dec 12, 2017
Journal Biochemical and Biophysical Research Communications
Print ISSN 0006-291X
Electronic ISSN 1090-2104
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 476
Issue 4
Pages 431-437
DOI https://doi.org/10.1016/j.bbrc.2016.05.140
Keywords CF; Epigenetics; CXCL8; BRD4
Public URL http://eprints.nottingham.ac.uk/id/eprint/48678
Publisher URL http://www.sciencedirect.com/science/article/pii/S0006291X16308622
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0