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Stimulus-dependent glucocorticoid-resistance of GM-CSF production in human cultured airway smooth muscle.


ABSTRACT: 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.

SUBMITTER: Tran T 

PROVIDER: S-EPMC1576125 | biostudies-other | 2005 May

REPOSITORIES: biostudies-other

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