TY - JOUR T1 - Inhibition of inflammatory gene expression by dexamethasone partly depends on the phosphatase, MKP-1 (DUSP1) JF - European Respiratory Journal JO - Eur Respir J VL - 42 IS - Suppl 57 SP - P730 AU - Suharsh Shah AU - Elizabeth King AU - Robert Newton Y1 - 2013/09/01 UR - http://erj.ersjournals.com/content/42/Suppl_57/P730.abstract N2 - Acting on the glucocorticoid receptor (GR), inhaled glucocorticoids (GCs) are a cornerstone in the treatment of asthma and suppress airway inflammation by reducing inflammatory gene expression. Traditionally, GR was believed to directly repress inflammatory gene transcription (transrepression). However, evidence also suggests that GC-dependent gene expression (transactivation) plays an important repressive role. Since repression of interleukin-8 (IL8) and GM-CSF (CSF2) by dexamethasone (Dex) depends on gene expression, we now examine the repressive role of Dex-induced mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 (DUSP1).METHODS: Pulmonary A549 epithelial cells were treated with IL-1β (1 ng/ml), with/without Dex (1 µM). Inflammatory gene expression was assessed by real-time PCR and ELISA, and MAPK activation by western blotting. Roles for MAPKs were explored with selective inhibitors and roles for MKP-1 were tested by over-expression and siRNA silencing.RESULTS: IL-1β rapidly increased inflammatory gene expression and this was MAPK-dependent. MKP-1 over-expression repressed expression of many IL-1β-induced inflammatory genes, including IL8 and CSF2. Inflammatory gene expression was significantly repressed by Dex in a manner that was modestly and transiently reversed by silencing of Dex-induced MKP-1.Conclusions: The apparently partial and transient role of MKP-1 in the repression of inflammatory gene expression, for example IL8 and CSF2, by Dex suggests that additional GC-induced gene products are also important. This provides a rational for functional screening of GC-inducible genes that may show repressive functions. ER -