The active metabolite of leflunomide, A77 1726, inhibits the production of prostaglandin E2, matrix metalloproteinase 1 and interleukin 6 in human fibroblast-like synoviocytes
The active metabolite of leflunomide, A77 1726, inhibits the production of prostaglandin E2, matrix metalloproteinase 1 and interleukin 6 in human fibroblast-like synoviocytes
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DOI：
10.1093/rheumatology/keg038
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发表时间：
2003-01-01
期刊：
影响因子：
5.5
通讯作者：
Dayer, JM
中科院分区：
文献类型：
--
作者：
Burger, D;Begué-Pastor, N;Dayer, JM
目标。研究来氟米特活性代谢物a771726对成纤维细胞样滑膜细胞的影响。在类风湿性关节炎（RA）中，滑膜细胞通过产生金属蛋白酶（MMP）、前列腺素E-2 （PGE(2)）和白细胞介素（IL） 6参与组织破坏，它们参与细胞外基质降解、矿物相的吸收和破骨细胞介导的骨吸收。在A77 1726存在的情况下，用il -1 α或肿瘤坏死因子α (tnf - α)刺激人滑膜细胞。分析培养上清中间质胶原酶（MMP-1）、金属蛋白酶组织抑制剂（TIMP-1）、PGE(2)和IL-6的产生情况。分离总RNA，分析MMP-1、环氧化酶-2 （COX-2）和IL-6 mrna的稳态水平。A77 1726对tnf - α和il -1 α激活的滑膜细胞产生PGE(2)的抑制作用中位浓度（IC50）分别为7和3个muM。相比之下，高A77 1726浓度（bbb10 muM）抑制了MMP-1和IL-6的产生，而TIMP-1不受影响。抑制MMP-1和IL-6的产生是由于已知的A77 1726对嘧啶合成的抑制作用，因为加入尿嘧啶可以逆转这种抑制作用。但这并不适用于PGE(2)的产生，A77 1726直接作用于COX-2可以抑制PGE(2)的产生，这可以从培养基中底物（花生四烯酸）的增加中看出。本研究表明来氟米特对RA患者的一些有益作用可能是由于抑制滑膜细胞中PGE(2)、IL-6和MMP-1的产生。这种作用，加上其对T淋巴细胞功能的多重抑制作用，可能是来氟米特治疗的RA患者疾病进展率显著降低的原因。
Objectives. To investigate the effects of the active metabolite of leflunomide, A77 1726, on fibroblast-like synoviocytes. In rheumatoid arthritis (RA) synoviocytes participate in tissue destruction by producing metalloproteinases (MMP), prostaglandin E-2 (PGE(2)) and interleukin (IL) 6, which are involved in extracellular matrix degradation, resorption of the mineral phase and osteoclast-mediated bone resorption.Methods. Human synoviocytes were stimulated with IL-1alpha or tumour necrosis factor alpha (TNF-alpha) in the presence of A77 1726. Culture supernatants were analysed for production of interstitial collagenase (MMP-1), tissue-inhibitor of metalloproteinases 1 (TIMP-1), PGE(2) and IL-6. Total RNA was isolated and analysed for steady-state levels of MMP-1, cyclooxygenase-2 (COX-2) and IL-6 mRNA.Results. A77 1726 inhibited the production of PGE(2) in synoviocytes activated by TNF-alpha and IL-1alpha with median inhibitory concentrations (IC50) of 7 and 3 muM respectively. In contrast, MMP-1 and IL-6 production was inhibited at high A77 1726 concentrations (>10 muM), whereas TIMP-1 was not affected. The inhibition of MMP-1 and IL-6 production was due to the known inhibitory effect of A77 1726 on pyrimidine synthesis, as it was reversed by the addition of uridine. This did not apply to PGE(2) production, which was inhibited via direct action of A77 1726 on COX-2, as shown by the increasing amount of substrate (arachidonic acid) in the culture medium.Conclusion. This study shows that some of the beneficial effect of leflunomide in RA patients may be due to the inhibition of PGE(2), IL-6 and MMP-1 production in synoviocytes. This effect, coupled with its multiple inhibitory effects on T lymphocyte functions, might account for the significant reduction in the rate of disease progression in RA patients treated with leflunomide.