Brd4 is essential for IL-1β-induced inflammation in human airway epithelial cells.

<h4>Background</h4>Chronic inflammation and oxidative stress are key features of chronic obstructive pulmonary disease (COPD). Oxidative stress enhances COPD inflammation under the control of the pro-inflammatory redox-sensitive transcription factor nuclear factor-kappaB (NF-κB). Histone...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Younis M Khan, Paul Kirkham, Peter J Barnes, Ian M Adcock
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b6e773be28c1451d99fffa7e881c7161
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:b6e773be28c1451d99fffa7e881c7161
record_format	dspace
spelling	oai:doaj.org-article:b6e773be28c1451d99fffa7e881c71612021-11-18T08:21:48ZBrd4 is essential for IL-1β-induced inflammation in human airway epithelial cells.1932-620310.1371/journal.pone.0095051https://doaj.org/article/b6e773be28c1451d99fffa7e881c71612014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24759736/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Chronic inflammation and oxidative stress are key features of chronic obstructive pulmonary disease (COPD). Oxidative stress enhances COPD inflammation under the control of the pro-inflammatory redox-sensitive transcription factor nuclear factor-kappaB (NF-κB). Histone acetylation plays a critical role in chronic inflammation and bromodomain and extra terminal (BET) proteins act as "readers" of acetylated histones. Therefore, we examined the role of BET proteins in particular Brd2 and Brd4 and their inhibitors (JQ1 and PFI-1) in oxidative stress- enhanced inflammation in human bronchial epithelial cells.<h4>Methods</h4>Human primary epithelial (NHBE) cells and BEAS-2B cell lines were stimulated with IL-1β (inflammatory stimulus) in the presence or absence of H2O2 (oxidative stress) and the effect of pre-treatment with bromodomain inhibitors (JQ1 and PFI-1) was investigated. Pro-inflammatory mediators (CXCL8 and IL-6) were measured by ELISA and transcripts by RT-PCR. H3 and H4 acetylation and recruitment of p65 and Brd4 to the native IL-8 and IL-6 promoters was investigated using chromatin immunoprecipitation (ChIP). The impact of Brd2 and Brd4 siRNA knockdown on inflammatory mediators was also investigated.<h4>Result</h4>H2O2 enhanced IL1β-induced IL-6 and CXCL8 expression in NHBE and BEAS-2B cells whereas H2O2 alone did not have any affect. H3 acetylation at the IL-6 and IL-8 promoters was associated with recruitment of p65 and Brd4 proteins. Although p65 acetylation was increased this was not directly targeted by Brd4. The BET inhibitors JQ1 and PFI-1 significantly reduced IL-6 and CXCL8 expression whereas no effect was seen with the inactive enantiomer JQ1(-). Brd4, but not Brd2, knockdown markedly reduced IL-6 and CXCL8 release. JQ1 also inhibited p65 and Brd4 recruitment to the IL-6 and IL-8 promoters.<h4>Conclusion</h4>Oxidative stress enhanced IL1β-induced IL-6 and CXCL8 expression was significantly reduced by Brd4 inhibition. Brd4 plays an important role in the regulation of inflammatory genes and provides a potential novel anti-inflammatory target.Younis M KhanPaul KirkhamPeter J BarnesIan M AdcockPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e95051 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Younis M Khan Paul Kirkham Peter J Barnes Ian M Adcock Brd4 is essential for IL-1β-induced inflammation in human airway epithelial cells.
description	<h4>Background</h4>Chronic inflammation and oxidative stress are key features of chronic obstructive pulmonary disease (COPD). Oxidative stress enhances COPD inflammation under the control of the pro-inflammatory redox-sensitive transcription factor nuclear factor-kappaB (NF-κB). Histone acetylation plays a critical role in chronic inflammation and bromodomain and extra terminal (BET) proteins act as "readers" of acetylated histones. Therefore, we examined the role of BET proteins in particular Brd2 and Brd4 and their inhibitors (JQ1 and PFI-1) in oxidative stress- enhanced inflammation in human bronchial epithelial cells.<h4>Methods</h4>Human primary epithelial (NHBE) cells and BEAS-2B cell lines were stimulated with IL-1β (inflammatory stimulus) in the presence or absence of H2O2 (oxidative stress) and the effect of pre-treatment with bromodomain inhibitors (JQ1 and PFI-1) was investigated. Pro-inflammatory mediators (CXCL8 and IL-6) were measured by ELISA and transcripts by RT-PCR. H3 and H4 acetylation and recruitment of p65 and Brd4 to the native IL-8 and IL-6 promoters was investigated using chromatin immunoprecipitation (ChIP). The impact of Brd2 and Brd4 siRNA knockdown on inflammatory mediators was also investigated.<h4>Result</h4>H2O2 enhanced IL1β-induced IL-6 and CXCL8 expression in NHBE and BEAS-2B cells whereas H2O2 alone did not have any affect. H3 acetylation at the IL-6 and IL-8 promoters was associated with recruitment of p65 and Brd4 proteins. Although p65 acetylation was increased this was not directly targeted by Brd4. The BET inhibitors JQ1 and PFI-1 significantly reduced IL-6 and CXCL8 expression whereas no effect was seen with the inactive enantiomer JQ1(-). Brd4, but not Brd2, knockdown markedly reduced IL-6 and CXCL8 release. JQ1 also inhibited p65 and Brd4 recruitment to the IL-6 and IL-8 promoters.<h4>Conclusion</h4>Oxidative stress enhanced IL1β-induced IL-6 and CXCL8 expression was significantly reduced by Brd4 inhibition. Brd4 plays an important role in the regulation of inflammatory genes and provides a potential novel anti-inflammatory target.
format	article
author	Younis M Khan Paul Kirkham Peter J Barnes Ian M Adcock
author_facet	Younis M Khan Paul Kirkham Peter J Barnes Ian M Adcock
author_sort	Younis M Khan
title	Brd4 is essential for IL-1β-induced inflammation in human airway epithelial cells.
title_short	Brd4 is essential for IL-1β-induced inflammation in human airway epithelial cells.
title_full	Brd4 is essential for IL-1β-induced inflammation in human airway epithelial cells.
title_fullStr	Brd4 is essential for IL-1β-induced inflammation in human airway epithelial cells.
title_full_unstemmed	Brd4 is essential for IL-1β-induced inflammation in human airway epithelial cells.
title_sort	brd4 is essential for il-1β-induced inflammation in human airway epithelial cells.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/b6e773be28c1451d99fffa7e881c7161
work_keys_str_mv	AT younismkhan brd4isessentialforil1binducedinflammationinhumanairwayepithelialcells AT paulkirkham brd4isessentialforil1binducedinflammationinhumanairwayepithelialcells AT peterjbarnes brd4isessentialforil1binducedinflammationinhumanairwayepithelialcells AT ianmadcock brd4isessentialforil1binducedinflammationinhumanairwayepithelialcells
_version_	1718421883726069760

Brd4 is essential for IL-1β-induced inflammation in human airway epithelial cells.

Ejemplares similares