Source: International Congress 2014 – New treatments for cough, asthma, COPD and ILDs
Disease area: Airway diseases

Abstract

RationaleIncreased airway smooth muscle (ASM) mass contributes to chronic airflow obstruction, chronic airway inflammation and airway wall remodelling. The novel chemical probe for BET bromodomians (JQ1/SGCBD01) was more potent at inhibiting TGF-b-induced ASM cell proliferation, IL-6 and CXCL8 release in cells from healthy individuals than in cells from non-severe and severe asthma. JQ1 can affect c-Myc expression or c-Myc association with proliferative gene promoters. Here, we compared the anti-inflammatory effects of JQ1 with that of a specific c-Myc inhibitor in ASM cells from asthmatics.MethodsASM cells were grown from healthy subjects and severe or non-severe asthmatics. Cells were pre-treated with the c-Myc inhibitor 10058-F4 or with JQ1 before being stimulated with FCS±TGF-b. IL-6 and CXCL8 secretion and cell proliferation were measured by ELISAs. mRNA expression was examined by RT-qPCR. Chromatin immunoprecipitation (ChIP) was performed using a specific c-Myc antibody and PCR primers against transcriptional start site of the IL-6 and CXCL8 promoters.Results10058-F4 inhibited ASM proliferation with no effect upon IL-6 or CXCL8 release. JQ1 had no effect on FCS+TGF-b-induced c-Myc expression. ChIP analysis found association of c-Myc with either the IL6 or CXCL8 promoters in ASM cells at baseline or following stimulation with FCS+TGF-b in the presence or absence of JQ1.ConclusionIL-6 and CXCL8 release from ASM cells is not affected by inhibition of c-Myc which corresponded with the failure to show c-Myc association with IL6 and CXCL8 promoters. The effect of JQ1 on c-Myc expression seen in cancerous cells and non-primary cells is different from that seen in primary asthmatic ASM cells.

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Citations should be made in the following way:
M. Perry, A. Durham, G. Sehra, I. Adcock, F. Chung (London, United Kingdom). The effect of JQ1/SGCBD01 upon c-Myc in human airway smooth muscle in asthma. Eur Respir J 2014; 44: Suppl. 58, 1512

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