Differential inhibition of thrombin- and EGF-stimulated human cultured airway smooth muscle proliferation by glucocorticoids.
The present study compared the effects of glucocorticoids on thrombin- and EGF-stimulated proliferation in human cultured airway smooth muscle (ASM) to identify pathways that may be differentially regulated by glucocorticoids. Mitogenic responses to thrombin were inhibited by extracellular-regulated kinase (ERK 1/2) and phosphoinositide 3-kinase (PI3K) inhibitors, whereas mitogenic responses to EGF were inhibited by ERK 1/2 and PI3K inhibitors as well as by the p38 mitogen activated protein kinase inhibitor, SB203580 (10 microM). Mitogenic responses to thrombin were more sensitive to inhibition by dexamethasone (Dex) or fluticasone propionate (FP) than were those to EGF. Elevated cyclin D1 protein and mRNA levels induced by thrombin and EGF were attenuated equally by glucocorticoids. The protein or mRNA levels of the cyclin-dependent kinase inhibitors (cdki) p21(Cip1), p27(Kip1) were unaffected by Dex treatment of ASM cells treated with mitogens. The resistance of EGF-induced proliferation to inhibition by glucocorticoids is not associated with a failure to regulate cyclin D1 induction, nor does it appear to be explained by differential regulation of the levels of the cdki's, p21(Cip1) and p27(Kip1).
Department of Pharmacology, University of Melbourne, Melbourne, Vic. 3010, Australia.
Ross
R
Vlahos
Kian Soon
KS
Lee
Elizabeth
E
Guida
Darren J
DJ
Fernandes
John W
JW
Wilson
Alastair G
AG
Stewart
D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D005938:Glucocorticoids; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D003907:Dexamethasone; D004247:DNA; D013917:Thrombin; D013936:Thymidine