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 (MAPK) inhibitor

• Published in: Arthritis research & therapy Vol. 6; no. 4; pp. R384 - R392
• Main Authors: Westra, Johanna, Doornbos-van der Meer, Berber, de Boer, Peter, van Leeuwen, Miek A, van Rijswijk, Martin H, Limburg, Pieter C
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 01.01.2004; BioMed Central
• Subjects: Cell Differentiation - drug effects; Cells, Cultured; Cyclooxygenase 2; Cytokines - biosynthesis; Gene Expression Regulation - drug effects; Gene Expression Regulation, Enzymologic - drug effects; Imidazoles - pharmacology; Interleukin-8 - genetics; Intracellular Signaling Peptides and Proteins; Isoenzymes - genetics; Macrophages - enzymology; Macrophages - physiology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Matrix Metalloproteinases - biosynthesis; Mitogen-Activated Protein Kinases; Monocytes - enzymology; Monocytes - physiology; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; Prostaglandin-Endoperoxide Synthases - genetics; Protein-Serine-Threonine Kinases - metabolism; Pyridines - pharmacology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 1478-6354; 1478-6362; 1478-6354
• DOI: 10.1186/ar1204

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-1beta, 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.