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

• Published in: British journal of pharmacology Vol. 145; no. 1; pp. 123 - 131
• Main Authors: Tran, Thai, Fernandes, Darren J, Schuliga, Michael, Harris, Trudi, Landells, Linda, Stewart, Alastair G
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2005; Nature Publishing
• Subjects: airway smooth muscle; Androstadienes - pharmacology; Biological and medical sciences; Cells, Cultured; Dexamethasone - pharmacology; Fluticasone; Gene Expression - drug effects; glucocorticoids; Glucocorticoids - pharmacology; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Humans; Hydrocortisone - pharmacology; Interleukin-1 - physiology; interleukin‐1α; Medical sciences; mRNA stability; Muscle, Smooth - drug effects; Muscle, Smooth - metabolism; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38MAPK; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Respiratory System - cytology; Respiratory System - drug effects; Respiratory System - metabolism; RNA, Messenger - metabolism; thrombin; Thrombin - physiology; Human; Stability; Serine endopeptidases; Hemostatic; Enzyme; Cytokine; Interleukin 1α; airway smooth muscle; Smooth muscle; Thrombin; interleukin-1α; Respiratory system; Glucocorticoid; Resistance; Respiratory tract; Peptidases; Messenger RNA; Hydrolases; glucocorticoids; Physicochemical properties; Granulocyte macrophage colony stimulating factor; p38MAPK; mRNA stability
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706174

1 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‐1α‐stimulated GM‐CSF production in human ASM cells. 2 Although IL‐1α stimulated three‐fold higher levels of GM‐CSF mRNA and protein compared to thrombin, dexamethasone concentration‐dependently reduced IL‐1α‐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‐1α and thrombin stimulated NF‐κB‐dependent luciferase expression equally. Dexamethasone treatment reduced luciferase expression stimulated by both IL‐1α and thrombin. 4 The GM‐CSF mRNA half life was markedly prolonged by IL‐1α compared to thrombin. This IL‐1α‐induced GM‐CSF mRNA stability was prevented by either dexamethasone or the p38MAPK inhibitor, SB203580, neither of which influenced GM‐CSF mRNA stability in thrombin‐treated cells. Dexamethasone inhibited p38MAPK phosphorylation in IL‐1α‐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‐1α depends on inhibition of the involvement of p38MAPK‐induced increases in GM‐CSF message stability. British Journal of Pharmacology (2005) 145, 123–131. doi:10.1038/sj.bjp.0706174