Strong inhibition of TNF-[alpha] production and inhibition of IL-8 and COX-2 mRNA expression in monocyte-derived macrophages by RWJ 67657, a p38 mitogen-activated protein kinase inhibitor

In inflammatory processes, the p38 mitogen-activated protein kinase (MAPK) signal transduction route regulates production and expression of cytokines and other inflammatory mediators. Tumor necrosis factor [alpha] (TNF-[alpha]) is a pivotal cytokine in rheumatoid arthritis and its production in macrophages is under control of the p38 MAPK route. Inhibition of the p38 MAPK route may inhibit production not only of TNF-[alpha], but also of other inflammatory mediators produced by macrophages, and indirectly of inflammatory mediators by other cells induced by TNF-[alpha] stimulation. Here we investigate the effects of RWJ 67657, a p38 MAPK inhibitor, on mRNA expression and protein production of TNF-[alpha] and other inflammatory mediators, in monocyte-derived macrophages. A strong inhibition of TNF-[alpha] was seen at pharmacologically relevant concentrations of RWJ 67657, but also inhibition of mRNA expression of IL-1[beta], IL-8, and cyclooxygenase-2 was shown. Furthermore, it was shown that monocyte-derived macrophages have a high constitutive production of matrix metalloproteinase 9, which is not affected by p38 MAPK inhibition. The results presented here may have important implications for the treatment of rheumatoid arthritis. Keywords: COX-2, matrix metalloproteinase, monocyte-derived macrophage, p38 MAPK inhibitor, TNF-[alpha]