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INFLAMMATION AND IMMUNOPHARMACOLOGY

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

Respiratory Pharmacology Group, Airway Diseases, Imperial College School of Medicine, National Heart and Lung Institute, Chelsea, London, United Kingdom (M.A.B., S.W., K.M., M.C.C., E.L.H., M.G.B.); and Royal Brompton and Harefield Hospital, London, United Kingdom (S.H.-Y.)

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)-1H-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 (TNF) protein production without impacting on nuclear factor B pathway activation or TNF 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.

Address correspondence to: Professor Maria G. Belvisi, Respiratory Pharmacology, Airway Diseases, Imperial College School of Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK. E-mail: m.belvisi{at}imperial.ac.uk

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