Second-Generation Inhibitors Demonstrate the Involvement of p38 Mitogen-Activated Protein Kinase in Post-Transcriptional Modulation of Inflammatory Mediator Production in Human and Rodent Airways

• Published in: The Journal of pharmacology and experimental therapeutics 2006-03, Vol.316 (3), p.1318-1327
• Main Authors: Mark A. Birrell, Sissie Wong, Kerryn McCluskie, Matthew C. Catley, Elizabeth L. Hardaker, Saleem Haj-Yahia, Maria G. Belvisi
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Cytokines - biosynthesis; Dexamethasone - pharmacology; Humans; Imidazoles - pharmacology; Inflammation Mediators - metabolism; Lipopolysaccharides - pharmacology; Lung - metabolism; Macrophages - metabolism; Male; Monocytes - metabolism; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - physiology; Protein Kinase Inhibitors - pharmacology; Pyrimidines - pharmacology; Rats; Transcription, Genetic - drug effects
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.093310

The exact role of p38 mitogen-activated protein kinase (MAPK) in the expression of inflammatory cytokines is not clear; it may regulate transcriptionally, post-transcriptionally, translationally, or post-translationally. The involvement of one or more of these mechanisms has been suggested to depend on the particular cytokine, the cell type studied, and the specific stimulus used. Interpretation of some of the published data is further complicated by the use of inhibitors such as 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1 H -imidazole (SB 203580) used at single, high concentrations. The aim of this study was to determine the impact of two second-generation p38 MAPK inhibitors on the expression of a range of inflammatory cytokines at the gene and protein levels in human cultured cells. Similar assessment of the impact of these compounds on inflammatory cytokine expression in a preclinical in vivo model of airway inflammation was performed. The results in THP-1 cells and primary airway macrophages clearly show that protein expression is inhibited at much lower concentrations of inhibitor than are needed to impact on gene expression. In the rodent model, both compounds, at doses that cause maximal inhibition of cellular recruitment, inhibit tumor necrosis factor α (TNFα) protein production without impacting on nuclear factor κB pathway activation or TNFα gene expression. In summary, the data shown here demonstrate that, although at high compound concentrations there is some level of transcriptional regulation, the predominant role of p38 MAPK in cytokine production is at the translational level. These data question whether the effect of p38 inhibitors on gene transcription is related to their potential therapeutic role as anti-inflammatory compounds.