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Formoterol counteracts the inhibitory effect of cigarette smoke on glucocorticoid-induced leucine zipper (GILZ) transactivation in human bronchial smooth muscle cells.
Marchini, Gessica; Carnevali, Silvia; Facchinetti, Fabrizio.
Afiliação
  • Marchini G; Department of Pharmacology and Toxicology, Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A., Parma, Italy.
  • Carnevali S; Department of Pharmacology and Toxicology, Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A., Parma, Italy.
  • Facchinetti F; Department of Pharmacology and Toxicology, Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A., Parma, Italy. Electronic address: f.facchinetti@chiesi.com.
Eur J Pharmacol ; 850: 8-14, 2019 May 05.
Article em En | MEDLINE | ID: mdl-30753866
ABSTRACT
Cigarette smokers with asthma and chronic obstructive pulmonary disease (COPD) are less responsive to glucocorticoids (GCs). The anti-inflammatory action of GCs depends also on their ability to transactivate genes such as GC-induced leucine zipper (GILZ). We investigated the effects of aqueous cigarette smoke extract (CSE) on GILZ transactivation evoked by 17-beclomethasone monopropionate (BMP) or fluticasone propionate (FP) in the presence or absence of the long acting ß2-adrenoceptor agonist (LABA) bronchodilator formoterol or salmeterol in human primary cultures of human bronchial smooth muscle cells (HBSMC). We monitored GC receptor Ser211 phosphorylation by western blot analysis and GC receptor nuclear translocation by immunostaining followed high-content imaging analysis. BMP, as well as FP, induced GILZ expression in a concentration-dependent manner (EC50 of 0.87 and 0.16 nM respectively). Pre-incubation with CSE inhibited GC-evoked GILZ transactivation (>50%), GC receptor Ser211 phosphorylation and nuclear translocation. Both formoterol and salmeterol counteracted the effect of CSE on GC-induced GILZ expression but not on nuclear translocation or phosphorylation. The effect of formoterol was mimicked by the cAMP-elevating agent forskolin and blocked by ICI 118,551, a selective ß2-adrenoceptor antagonist. Pre-incubation with TNF-α also reduced GC-evoked GILZ transactivation but was not counteracted by formoterol undercovering a different responsiveness to LABAs of TNF-α in comparison to CSE. In sum, CSE inhibits GC-evoked transactivation of GILZ and such effect is counteracted by LABAs, through ß2-adrenoceptors and a cAMP-dependent mechanism. This study sheds light on a mechanism underlying complementary interactions between LABAs and inhaled GCs that could be relevant in smokers with asthma and COPD.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Brônquios / Ativação Transcricional / Miócitos de Músculo Liso / Fumarato de Formoterol / Fumar Cigarros Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Brônquios / Ativação Transcricional / Miócitos de Músculo Liso / Fumarato de Formoterol / Fumar Cigarros Idioma: En Ano de publicação: 2019 Tipo de documento: Article