title: Corticosteroid-Induced MKP-1 Represses Pro-Inflammatory Cytokine Secretion by Enhancing Activity of Tristetraprolin (TTP) in ASM Cells.
abstract: Exaggerated cytokine secretion drives pathogenesis of a number of chronic inflammatory diseases, including asthma. Anti-inflammatory pharmacotherapies, including corticosteroids, are front-line therapies and although they have proven clinical utility, the molecular mechanisms responsible for their actions are not fully understood. The corticosteroid-inducible gene, mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1, DUSP1) has emerged as a key molecule responsible for the repressive effects of steroids. MKP-1 is known to deactivate p38 MAPK phosphorylation and can control the expression and activity of the mRNA destabilizing protein-tristetraprolin (TTP). But whether corticosteroid-induced MKP-1 acts via p38 MAPK-mediated modulation of TTP function in a pivotal airway cell type, airway smooth muscle (ASM), was unknown. While pretreatment of ASM cells with the corticosteroid dexamethasone (preventative protocol) is known to reduce ASM synthetic function in vitro, the impact of adding dexamethasone after stimulation (therapeutic protocol) had not been explored. Whether dexamethasone modulates TTP in a p38 MAPK-dependent manner in this cell type was also unknown. We address this herein and utilize an in vitro model of asthmatic inflammation where ASM cells were stimulated with the pro-asthmatic cytokine tumor necrosis factor (TNF) and the impact of adding dexamethasone 1 h after stimulation assessed. IL-6 mRNA expression and protein secretion was significantly repressed by dexamethasone acting in a temporally distinct manner to increase MKP-1, deactivate p38 MAPK, and modulate TTP phosphorylation status. In this way, dexamethasone-induced MKP-1 acts via p38 MAPK to switch on the mRNA destabilizing function of TTP to repress pro-inflammatory cytokine secretion from ASM cells. J. Cell. Physiol. 231: 2153-2158, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Pavan
authors.initials: P
authors.lastname: Prabhala
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Kristin
authors.initials: K
authors.lastname: Bunge
authors.affiliation: Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ge
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D000305:Adrenal Cortex Hormones / Q000378:metabolism / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051816:Tristetraprolin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D051816:Tristetraprolin; D003907:Dexamethasone; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1