Westra Johanna, Doornbos-van der Meer Berber, de Boer Peter, van Leeuwen Miek A, van Rijswijk Martin H, Limburg Pieter C
Department of Rheumatology, University Hospital Groningen, Groningen, The Netherlands.
Arthritis Res Ther. 2004;6(4):R384-92. doi: 10.1186/ar1204. Epub 2004 Jun 21.
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.
在炎症过程中，p38丝裂原活化蛋白激酶（MAPK）信号转导途径调节细胞因子及其他炎症介质的产生和表达。肿瘤坏死因子α（TNF-α）是类风湿性关节炎中的一种关键细胞因子，其在巨噬细胞中的产生受p38 MAPK途径调控。抑制p38 MAPK途径不仅可能抑制TNF-α的产生，还可能抑制巨噬细胞产生的其他炎症介质，以及间接抑制由TNF-α刺激诱导的其他细胞产生的炎症介质。在此，我们研究p38 MAPK抑制剂RWJ 67657对单核细胞衍生巨噬细胞中TNF-α及其他炎症介质的mRNA表达和蛋白质产生的影响。在与RWJ 67657药理相关的浓度下，观察到TNF-α受到强烈抑制，同时还显示出IL-1β、IL-8和环氧化酶-2的mRNA表达受到抑制。此外，研究表明单核细胞衍生巨噬细胞中基质金属蛋白酶9的组成性产生较高，其不受p38 MAPK抑制的影响。本文呈现的结果可能对类风湿性关节炎的治疗具有重要意义。
