Second-Generation Inhibitors Demonstrate The Involvement Of P38 Mitogen-Activated Protein Kinase In Post-Transcriptional Modulation Of In-Flammatory Mediator Production In Human And Rodent Airways
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 alpha (TNFalpha) protein
production without impacting on nuclear factor kappaB pathway activation
or TNFalpha 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.
Journal
Title
J Pharmacol Exp Ther. 2006 Mar;316(3):1318-27. Epub 2005 Dec 20.