Down-regulation of Cytokine-induced Interleukin-8 Requires Inhibition of p38 Mitogen-activated Protein Kinase (MAPK) via MAPK Phosphatase 1-dependent and -independent Mechanisms

• Published in: The Journal of biological chemistry 2011-05, Vol.286 (18), p.15998-16007
• Main Authors: Dauletbaev, Nurlan, Eklove, Daniel, Mawji, Nadir, Iskandar, Michele, Di Marco, Sergio, Gallouzi, Imed-Eddine, Lands, Larry C.
• Format: Article
• Language: English
• Subjects: Airway Epithelial Cells; Anti-Inflammatory Agents - pharmacology; Cell Line; Cellular Immune Response; Cystic Fibrosis; Cytokine; Dexamethasone; Dexamethasone - pharmacokinetics; Dual Specificity Phosphatase 1 - genetics; Dual Specificity Phosphatase 1 - metabolism; Enzyme Activation - drug effects; Enzyme Activation - physiology; Humans; Ibuprofen; Ibuprofen - pharmacology; Imidazoles - pharmacology; Immunology; Inflammation; Interleukin-8; Interleukin-8 - biosynthesis; Interleukin-8 - genetics; mRNA Stability; p38 MAPK; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Pyridines - pharmacology; RNA Stability - drug effects; RNA Stability - physiology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.205724

Down-regulation of overabundant interleukin (IL)-8 present in cystic fibrosis (CF) airways could ease excessive neutrophil burden and its deleterious consequences for the lung. IL-8 production in airway epithelial cells, stimulated with e.g. inflammatory cytokines IL-1β and tumor necrosis factor (TNF)-α, is regulated by several signaling pathways including nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK). We previously demonstrated that the anti-inflammatory drugs dexamethasone and ibuprofen suppress NF-κB; however, only dexamethasone down-regulates cytokine-induced IL-8, highlighting the importance of non-NF-κB mechanisms. Here, we tested the hypothesis that down-regulation of cytokine-induced IL-8 requires modulation of the MAPK phosphatase (MKP)-1/p38 MAPK/mRNA stability pathway. The effects of dexamethasone (5 nm) and ibuprofen (480 μm) on this pathway and IL-8 were studied in CF (CFTE29o−, CFBE41o−) and non-CF (1HAEo−) airway epithelial cells. We observed that dexamethasone, but not ibuprofen, destabilizes IL-8 mRNA and up-regulates MKP-1 mRNA. Further, siRNA silencing of MKP-1, via p38 MAPK, leads to IL-8 overproduction and diminishes the anti-IL-8 potential of dexamethasone. However, MKP-1 overexpression does not significantly alter IL-8 production. By contrast, direct inhibition of p38 MAPK (inhibitor SB203580) efficiently suppresses IL-8 with potency comparable with dexamethasone. Similar to dexamethasone, SB203580 decreases IL-8 mRNA stability. Dexamethasone does not affect p38 MAPK activation, which excludes its effects upstream of p38 MAPK. In conclusion, normal levels of MKP-1 are necessary for a full anti-IL-8 potential of pharmacological agents; however, efficient pharmacological down-regulation of cytokine-induced IL-8 also requires direct effects on p38 MAPK and mRNA stability independently of MKP-1.