Received for publication July 28, 2005.
Revised December 15, 2005.
Accepted for publication December 15, 2005.

Second generation inhibitors demonstrate the involvement of p38 MAP kinase in post-transcriptional modulation of inflammatory mediator production in human and rodent airways

Abstract

The exact role of p38 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 employed. Interpretation of some of the published data is further complicated by the use of inhibitors such as SB 203580 employed 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 level in human cultured cells. Similar assessment of the impact of these compounds on inflammatory cytokine expression in a pre-clinical 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 TNF; protein production without impacting on NF-B pathway activation or TNF; gene expression. In summary, the data shown here demonstrates 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.

Key words: airway inflammation, interleukin 1 beta, lipopolysaccharide (LPS), neutrophilia, p38 MAP kinase, tumor necrosis factor alpha

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