Effects of RWJ 67657, a p38 mitogen activated protein kinase (MAPK) inhibitor, on the production of inflammatory mediators by rheumatoid synovial fibroblasts.
OBJECTIVE
To investigate the effect of the p38 mitogen activated protein kinase (MAPK) inhibitor RWJ 67657 on inflammatory mediator production by rheumatoid synovial fibroblasts (RSF).


METHODS
RSF were pretreated with RWJ 67657 and stimulated with TNF alpha and/or IL-1 beta. Protein levels and mRNA expression of MMP-1, MMP-3, TIMP-1, IL-6, and IL-8 were determined, as was mRNA expression of COX-2 and ADAMTS-4.


RESULTS
MMP-3 production was significantly inhibited at 1 microM RWJ 67657 and MMP-1 production at 10 microM, while TIMP-1 production was not inhibited. Inhibition of IL-6 and IL-8 protein production was seen at 0.1 microM RWJ 67657. Expression profiles of mRNA were in accordance with protein production. Inhibition of COX-2 mRNA expression occurred at 0.01 microM RWJ 67657.


CONCLUSIONS
RWJ 67657 inhibits major proinflammatory mediator production in stimulated RSF at pharmacologically relevant concentrations. These findings could have important relevance for the treatment of rheumatoid arthritis.
Westra
J
J
Department of Rheumatology, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, Netherlands. j.westra@med.rug.nl
Limburg
P C
PC
de Boer
P
P
van Rijswijk
M H
MH
D051722:ADAM Proteins; D000071121:ADAMTS4 Protein; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000032:analysis; D016209:Interleukin-8 / Q000032:analysis; D007527:Isoenzymes / Q000235:genetics; D020781:Matrix Metalloproteinase 1 / Q000032:analysis; D019278:Matrix Metalloproteinase 3 / Q000032:analysis; D008565:Membrane Proteins; D008666:Metalloendopeptidases / Q000032:analysis; D010766:Phosphorylation / Q000187:drug effects; D011348:Procollagen N-Endopeptidase; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D013583:Synovial Membrane / Q000187:drug effects* / Q000276:immunology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D007093:Imidazoles; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D007527:Isoenzymes; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C400277:RWJ 67657; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D011348:Procollagen N-Endopeptidase; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human