BET bromodomains regulate transforming growth factor-β-induced proliferation and cytokine release in asthmatic airway smooth muscle

Mark M. Perry, Andrew L. Durham, Philip J. Austin, Ian M. Adcock, Kian Fan Chung

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Abstract

Airway smooth muscle (ASM) mass is increased in asthma, and ASM cells from patients with asthma are hyperproliferative and release more IL-6 and CXCL8. The BET (bromo- and extra-terminal) family of proteins (Brd2, Brd3, and Brd4) govern the assembly of histone acetylation-dependent chromatin complexes. We have examined whether they modulate proliferation and cytokine expression in asthmatic ASM cells by studying the effect of BET bromodomain mimics JQ1/SGCBD01 and I-BET762. ASM cells from healthy individuals and nonsevere and severe asthmatics were pretreated with JQ1/SGCBD01 and I-BET762 prior to stimulation with FCS and TGF-β. Proliferation was measured by BrdU incorporation. IL-6 and CXCL8 release was measured by ELISA, and mRNA expression was measured by quantitative RT-PCR. ChIP using a specific anti-Brd4 antibody and PCR primers directed against the transcriptional start site of IL-6 and CXCL8 gene promoters was performed. Neither JQ1/SGCBD01 nor I-BET762 had any effect on ASM cell viability. JQ1/SGCBD01 and I-BET762 inhibited FCS+TGF-β-induced ASM cell proliferation and IL-6 and CXCL8 release in healthy individuals (≥ 30 nM) and in nonsevere and severe asthma patients (≥100 nM), with the latter requiring higher concentrations of these mimics. JQ1/SGCBD01 reduced Brd4 binding to IL8 and IL6 promoters induced by FCS+TGF-β. Mimics of BET bromodomains inhibit aberrant ASM cell proliferation and inflammation with lesser efficiency in those from asthmatic patients. They may be effective in reducing airway remodeling in asthma.
Original languageEnglish
Pages (from-to)9111-9121
Number of pages11
JournalThe Journal of Biological Chemistry
Volume290
Issue number14
Early online date19 Feb 2015
DOIs
Publication statusPublished - 3 Apr 2015
Externally publishedYes

Keywords

  • asthma
  • bromodomain-containing protein 4 (BRD4)
  • cell proliferation
  • interleukin 6 (IL-6)
  • Myc (c-Myc)
  • always smooth musscle
  • CXCL8
  • I-BET762
  • JQ1/SGCBD01
  • Wellcome Trust
  • 085935

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