title: Corticosteroids reduce IL-6 in ASM cells via up-regulation of MKP-1.
abstract: The mechanisms by which corticosteroids reduce airway inflammation are not completely understood. Traditionally, corticosteroids were thought to inhibit cytokines exclusively at the transcriptional level. Our recent evidence, obtained in airway smooth muscle (ASM), no longer supports this view. We have found that corticosteroids do not act at the transcriptional level to reduce TNF-alpha-induced IL-6 gene expression. Rather, corticosteroids inhibit TNF-alpha-induced IL-6 secretion by reducing the stability of the IL-6 mRNA transcript. TNF-alpha-induced IL-6 mRNA decays at a significantly faster rate in ASM cells pretreated with the corticosteroid dexamethasone (t(1/2) = 2.4 h), compared to vehicle (t(1/2) = 9.0 h; P < 0.05) (results are expressed as decay constants [k] [mean +/- SEM] and half-life [h]). Interestingly, the underlying mechanism of inhibition by corticosteroids is via the up-regulation of an endogenous mitogen-activated protein kinase (MAPK) inhibitor, MAPK phosphatase-1 (MKP-1). Corticosteroids rapidly up-regulate MKP-1 in a time-dependent manner (44.6 +/- 10.5-fold increase after 24 h treatment with dexamethasone; P < 0.05), and MKP-1 up-regulation was temporally related to the inhibition of TNF-alpha-induced p38 MAPK phosphorylation. Moreover, TNF-alpha acts via a p38 MAPK-dependent pathway to stabilize the IL-6 mRNA transcript (TNF-alpha, t(1/2) = 9.6 h; SB203580 + TNF-alpha, t(1/2) = 1.5 h), exogenous expression of MKP-1 significantly inhibits TNF-alpha-induced IL-6 secretion and MKP-1 siRNA reverses the inhibition of TNF-alpha-induced IL-6 secretion by dexamethasone. Taken together, these results suggest that corticosteroid-induced MKP-1 contributes to the repression of IL-6 secretion in ASM cells.
authors.affiliation: Respiratory Research Group, 1Faculty of Pharmacy and 2Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Timo
authors.initials: T
authors.lastname: Quante
authors.forename: Yee Ching
authors.initials: YC
authors.lastname: Ng
authors.forename: Emma E
authors.initials: EE
authors.lastname: Ramsay
authors.forename: Sheridan
authors.initials: S
authors.lastname: Henness
authors.forename: Jodi C
authors.initials: JC
authors.lastname: Allen
authors.forename: Johannes
authors.initials: J
authors.lastname: Parmentier
authors.forename: Qi
authors.initials: Q
authors.lastname: Ge
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D007093:Imidazoles; D015850:Interleukin-6; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C093642:SB 203580