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.
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.
Westra
Johanna
J
Department of Rheumatology, University Hospital Groningen, Groningen, The Netherlands. j.westra@med.rug.nl
Doornbos-van der Meer
Berber
B
de Boer
Peter
P
van Leeuwen
Miek A
MA
van Rijswijk
Martin H
MH
Limburg
Pieter C
PC
D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000201:enzymology* / Q000502:physiology*; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases; D009000:Monocytes / Q000201:enzymology / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
D051546:Cyclooxygenase 2; D016207:Cytokines; D007093:Imidazoles; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D020782:Matrix Metalloproteinases; D020928:Mitogen-Activated Protein Kinases; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C400277:RWJ 67657