Stimulus-dependent glucocorticoid-resistance of GM-CSF production in human cultured airway smooth muscle.
For a subpopulation of asthmatics, symptoms persist even with high doses of glucocorticoids. Glucocorticoids reduce the levels of the proinflammatory and fibrogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by human cultured airway smooth muscle (ASM). We have contrasted the effects of a synthetic glucocorticoid, dexamethasone, on thrombin- and IL-1alpha-stimulated GM-CSF production in human ASM cells. Although IL-1alpha stimulated three-fold higher levels of GM-CSF mRNA and protein compared to thrombin, dexamethasone concentration-dependently reduced IL-1alpha-stimulated GM-CSF more potently and to a greater extent than the response to thrombin. This pattern of glucocorticoid regulation was also observed at the GM-CSF mRNA level and was reproduced with other glucocorticoids such as fluticasone propionate. IL-1alpha and thrombin stimulated NF-kappa B-dependent luciferase expression equally. Dexamethasone treatment reduced luciferase expression stimulated by both IL-1alpha and thrombin. The GM-CSF mRNA half life was markedly prolonged by IL-1alpha compared to thrombin. This IL-1alpha-induced GM-CSF mRNA stability was prevented by either dexamethasone or the p38(MAPK) inhibitor, SB203580, neither of which influenced GM-CSF mRNA stability in thrombin-treated cells. Dexamethasone inhibited p38(MAPK) phosphorylation in IL-1alpha-stimulated ASM, whereas thrombin does not stimulate p38(MAPK) phosphorylation. These data suggest that the mechanism underlying the greater potency and efficacy of glucocorticoids in reducing GM-CSF synthesis stimulated by IL-1alpha depends on inhibition of the involvement of p38(MAPK)-induced increases in GM-CSF message stability.
Tran
Thai
T
Department of Pharmacology, University of Melbourne, Grattan St, Victoria 3010, Australia.
Fernandes
Darren J
DJ
Schuliga
Michael
M
Harris
Trudi
T
Landells
Linda
L
Stewart
Alastair G
AG
D000730:Androstadienes / Q000494:pharmacology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D000068298:Fluticasone; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D013917:Thrombin / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D000730:Androstadienes; D005938:Glucocorticoids; D007375:Interleukin-1; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000068298:Fluticasone; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; D006854:Hydrocortisone
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