The active metabolite of leflunomide, A77 1726, increases the production of IL-1 receptor antagonist in human synovial fibroblasts and articular chondrocytes
The active metabolite of leflunomide, A77 1726, increases the production of IL-1 receptor antagonist in human synovial fibroblasts and articular chondrocytes
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DOI：
10.1186/ar1157
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发表时间：
2004-01-01
影响因子：
4.9
通讯作者：
Guerne, PA
中科院分区：
文献类型：
--
作者：
Palmer, G;Burger, D;Guerne, PA
来氟米特是一种用于治疗类风湿性关节炎的免疫调节剂。本研究探讨来氟米特的活性代谢物A77 1726对人滑膜成纤维细胞和关节软骨细胞产生IL-1受体拮抗剂(IL-1ra)的影响。细胞与A771726单独或与促炎细胞因子联合孵育。用双抗体夹心法测定IL-1ra的产生。A771726单独作用不明显，但在IL-1β或肿瘤坏死因子-α存在的情况下，显著促进滑膜成纤维细胞和软骨细胞分泌IL-1ra。在滑膜成纤维细胞和去分化软骨细胞中，A771726还能增加IL-1β诱导的细胞裂解物中IL-1ra的产生。新鲜分离的软骨细胞不含明显的细胞内IL-1ra。A77 1726是已知的嘧啶合成和环氧合酶(COX)-2活性的抑制剂。外源性尿苷的加入不能显著改变A771726对IL-1ra产生的影响，提示该作用不是通过抑制嘧啶合成来实现的。吲哚美辛增加IL-1β诱导的滑膜成纤维细胞和去分化软骨细胞IL-1ra的分泌，提示抑制COX-2可能确实增加了IL-1β诱导的IL-1ra的产生。然而，吲哚美辛的刺激作用始终不如A77 1726有效。A77 1726在促炎细胞因子存在的情况下增加滑膜成纤维细胞和软骨细胞产生IL-1ra，因此可能具有软骨保护作用。A77 1726的作用可能部分是通过抑制COX-2来实现的，但其他机制可能也会刺激IL-1ra的产生。
Leflunomide is an immunomodulatory agent used for the treatment of rheumatoid arthritis. In this study, we investigated the effect of A77 1726 - the active metabolite of leflunomide on the production of IL-1 receptor antagonist (IL-1Ra) by human synovial fibroblasts and articular chondrocytes. Cells were incubated with A77 1726 alone or in combination with proinflammatory cytokines. IL-1Ra production was determined by ELISA. A77 1726 alone had no effect, but in the presence of IL-1beta or tumour necrosis factor-alpha it markedly enhanced the secretion of IL-1Ra in synovial fibroblasts and chondrocytes. The effect of A77 1726 was greatest at 100 mumol/l. In synovial fibroblasts and de-differentiated chondrocytes, A77 1726 also increased IL-1beta-induced IL-1Ra production in cell lysates. Freshly isolated chondrocytes contained no significant amounts of intracellular IL-1Ra. A77 1726 is a known inhibitor of pyrimidine synthesis and cyclo-oxygenase ( COX)- 2 activity. Addition of exogenous uridine did not significantly modify the effect of A77 1726 on IL-1Ra production, suggesting that it was not mediated by inhibition of pyrimidine synthesis. Indomethacin increased IL-1beta-induced IL-1Ra secretion in synovial fibroblasts and de-differentiated chondrocytes, suggesting that inhibition of COX-2 may indeed enhance IL-1beta-induced IL-1Ra production. However, the stimulatory effect of indomethacin was consistently less effective than that of A77 1726. A77 1726 increases IL-1Ra production by synovial fibroblasts and chondrocytes in the presence of proinflammatory cytokines, and thus it may possess chondroprotective effects. The effect of A77 1726 may be partially mediated by inhibition of COX-2, but other mechanisms likely concur to stimulate IL-1Ra production.