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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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Project description:To elucidate the regulation of glucocorticoid receptor (GR) signaling under pro-asthmatic conditions, cultured human airway smooth muscle (HASM) cells were treated with proinflammatory cytokines or GR ligands alone and in combination, and then examined for induced changes in ligand-dependent and -independent GR activation and downstream signaling events. Ligand stimulation with either cortisone or dexamethsone (DEX) acutely elicited GR translocation to the nucleus and, comparably, ligand-independent stimulation either with the Th2 cytokine, IL-13, or the pleiotropic cytokine combination, IL-1β/TNFα, also acutely evoked GR translocation. The latter response was potentiated by combined exposure of cells to GR ligand and cytokine. Similarly, treatment with either DEX or IL-13 alone induced GR phosphorylation at its serine-211 residue (GR(Ser211)), denoting its activated state, and combined treatment with DEX+IL-13 elicited heightened and sustained GR(Ser211) phosphorylation. Interestingly, the above ligand-independent GR responses to IL-13 alone were not associated with downstream GR binding to its consensus DNA sequence or GR transactivation, whereas both DEX-induced GR:DNA binding and transcriptional activity were significantly heightened in the presence of IL-13, coupled to increased recruitment of the transcriptional co-factor, MED14. The stimulated GR signaling responses to DEX were prevented in IL-13-exposed cells wherein GR(Ser211) phosphorylation was suppressed either by transfection with specific serine phosphorylation-deficient mutant GRs or treatment with inhibitors of the MAPKs, ERK1/2 and JNK. Collectively, these novel data highlight a heretofore-unidentified homeostatic mechanism in HASM cells that involves pro-asthmatic cytokine-driven, MAPK-mediated, non-ligand-dependent GR activation that confers heightened glucocorticoid ligand-stimulated GR signaling. These findings raise the consideration that perturbations in this homeostatic cytokine-driven GR signaling mechanism may be responsible, at least in part, for the insensirtivity to glucocorticoid therapy that is commonly seen in individuals with severe asthma.

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

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