Takahashi S, Inoue T, Higaki M, Mizushima Y
Institute of Medical Science, St. Marianna University, School of Medicine, Kanagawa, Japan.
Drugs Exp Clin Res. 1998;24(2):67-71.
KE-298 is a novel antirheumatic drug which suppresses various animal models of arthritis by inhibiting the production of inflammatory cytokines. In a phase II study of rheumatoid arthritis patients, ingestion of KE-298 led to significant improvements in the Lansbury index. The objective of the present study was to clarify the effects of KE-298 against synovium functions, using rheumatoid arthritis synoviocytes. We investigated the effects of KE-298 on the production of matrix metalloproteinases and tissue inhibitor-1 of metalloproteinases and bone absorptive mediators including interleukin (IL)-6 and prostaglandin (PG) E2 in tumor necrosis factor (TNF)-alpha-stimulated rheumatoid arthritis synoviocytes. Rheumatoid arthritis synoviocytes were obtained from knee joints of rheumatoid arthritis patients and type B fibroblast-like synoviocytes were stimulated with TNF-alpha, with or without KE-298. The contents of metalloproteinases and tissue inhibitor-1 of metalloproteinases and IL-6 and PGE2 in culture media were measured by enzyme-linked immunosorbent assay. KE-298 significantly suppressed TNF-alpha-induced production of promatrix metalloproteinase-1 and IL-6, in a dose-dependent manner, but not that of tissue inhibitor-1 of metalloproteinases. The potential of KE-298 to suppress the production of matrix metalloproteinase-1 and IL-6 may explain its efficacy on rheumatoid arthritis.
KE-298是一种新型抗风湿药物，它通过抑制炎性细胞因子的产生来抑制各种关节炎动物模型。在一项针对类风湿性关节炎患者的II期研究中，服用KE-298使兰斯伯里指数有显著改善。本研究的目的是利用类风湿性关节炎滑膜细胞阐明KE-298对滑膜功能的影响。我们研究了KE-298对肿瘤坏死因子（TNF）-α刺激的类风湿性关节炎滑膜细胞中基质金属蛋白酶、金属蛋白酶组织抑制剂-1以及包括白细胞介素（IL）-6和前列腺素（PG）E2在内的骨吸收介质产生的影响。类风湿性关节炎滑膜细胞取自类风湿性关节炎患者的膝关节，B型成纤维细胞样滑膜细胞用TNF-α刺激，同时加入或不加入KE-298。通过酶联免疫吸附测定法测量培养基中基质金属蛋白酶、金属蛋白酶组织抑制剂-1、IL-6和PGE2的含量。KE-298以剂量依赖的方式显著抑制TNF-α诱导的前基质金属蛋白酶-1和IL-6的产生，但对金属蛋白酶组织抑制剂-1的产生没有抑制作用。KE-298抑制基质金属蛋白酶-1和IL-6产生的潜力可能解释了其对类风湿性关节炎的疗效。
