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

Arthritis Research & Therapy
Johanna WestraPieter C Limburg

Abstract

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.

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Citations

Jul 11, 2009·Pharmacology·Barry L BurnetteJoseph Monahan
Jan 8, 2008·Arthritis Research & Therapy·Raimund W KinneGerd-R Burmester
Aug 13, 2013·TheScientificWorldJournal·Sarah Dubois Declercq, Roxane Pouliot
Dec 4, 2008·The American Journal of Chinese Medicine·Ting-Yu WangJi-Hui Tang
Jan 1, 2008·Expert Review of Clinical Immunology·Bozena Kaminska, Karolina Swiatek-Machado
May 9, 2009·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·H R BoumaT A Schuurs
Jun 30, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Toshio YoshizawaGary S Firestein
Mar 14, 2013·Journal of Cellular and Molecular Medicine·Derek H RosenzweigThomas M Quinn
May 8, 2019·Evidence-based Complementary and Alternative Medicine : ECAM·Mao-Qiang ManPeter M Elias
Dec 21, 2011·Chemical Biology & Drug Design·M Ahmed MesaikM Iqbal Choudhary
Jul 11, 2019·Infectious Disorders Drug Targets·Monu YadavParamjeet Malik
Dec 28, 2010·Clinica Chimica Acta; International Journal of Clinical Chemistry·Mehmet CoskunOle Haagen Nielsen
Oct 31, 2006·Seminars in Cell & Developmental Biology·Sharon BinghamIain P Chessell

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Methods Mentioned

BETA
flow cytometry
ELISA
density-gradient centrifugation
FCS
ELISAs
PCR

Software Mentioned

GraphPad
GraphPad Prism

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