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

1 For a subpopulation of asthmatics, symptoms persist even with high doses of glucocorticoids. Glucocorticoids reduce the levels of the proinflammatory and fibrogenic cytokine, granulocytemacrophage 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-1 alpha-stimulated GM-CSF production in human ASM cells. 2 Although IL-1 alpha stimulated three-fold higher levels of GM-CSF mRNA and protein compared to thrombin, dexamethasone concentration-dependently reduced IL-1 alpha-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. 3 IL-1 alpha and thrombin stimulated NF-kappa B-dependent luciferase expression equally. Dexamethasone treatment reduced luciferase expression stimulated by both IL-1 alpha and thrombin. 4 The GM-CSF mRNA half life was markedly prolonged by IL-1 alpha compared to thrombin. This IL-1 alpha-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-1 alpha-stimulated ASM, whereas thrombin does not stimulate p38MAPK phosphorylation. 5 These data suggest that the mechanism underlying the greater potency and efficacy of glucocorticoids in reducing GM-CSF synthesis stimulated by IL-1 alpha depends on inhibition of the involvement of p38(MAPK)-induced increases in GM-CSF message stability.