Regulation of airway smooth muscle alpha-actin expression by glucocorticoids.
Airway smooth muscle hypertrophy appears to be present in severe asthma. However, the effect of corticosteroids on airway smooth muscle cell size or contractile protein expression has not been studied. We examined the effects of dexamethasone, fluticasone, and salmeterol on contractile protein expression in transforming growth factor (TGF)-beta-treated primary bronchial smooth muscle cells. Dexamethasone and fluticasone, but not salmeterol, each reduced expression of alpha-smooth muscle actin and the short isoform of myosin light chain kinase. Steady-state alpha-actin mRNA level and stability were unchanged, consistent with posttranscriptional control. Fluticasone significantly decreased alpha-actin protein synthesis following treatment with the transcriptional inhibitor actinomycin D, indicative of an inhibitory effect on mRNA translation. Fluticasone also significantly increased alpha-actin protein turnover. Finally, fluticasone reduced TGF-beta-induced incorporation of alpha-actin into filamentous actin, cell length, and cell shortening in response to ACh and KCl. We conclude that glucocorticoids reduce human airway smooth muscle alpha-smooth muscle actin expression and incorporation into contractile filaments, as well as contractile function, in part by attenuation of mRNA translation and enhancement of protein degradation.
Goldsmith
Adam M
AM
Department of Pediatrics, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0688, USA.
Hershenson
Marc B
MB
Wolbert
Miguel P
MP
Bentley
J Kelley
JK
D000199:Actins / Q000235:genetics* / Q000378:metabolism*; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D000068298:Fluticasone; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000068299:Salmeterol Xinafoate; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000199:Actins; D000730:Androstadienes; D005938:Glucocorticoids; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000068299:Salmeterol Xinafoate; D003907:Dexamethasone; D000068298:Fluticasone; D000420:Albuterol