Division of Rheumatology, Department of Internal Medicine, 3rd Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, PR China.
Eur J Pharmacol. 2011 Nov 16;670(1):304-10. doi: 10.1016/j.ejphar.2011.07.045. Epub 2011 Aug 19.
Recent studies have reported elevated expression of cluster of differentiation (CD) 147 on CD14(+) monocytes of the peripheral blood of patients with active rheumatoid arthritis and a correlation of CD147 expression with Disease Activity Score. Thus, CD147 may be a new target for treatment of rheumatoid arthritis. Leflunomide is a disease-modifying antirheumatic drug that is commonly used to treat rheumatoid arthritis. The effect of leflunomide in blocking the up-regulation of CD147 and in blocking the down-regulation of metalloproteinases (MMP)-2 and MMP-9 in active macrophages has not yet been established. In this study we investigated the effect of A771726, the active metabolite of leflunomide, on expression of CD147 and on the gelatinolytic activity of MMP-2 and MMP-9 in phorbol myristate acetate (PMA) differentiated THP-1 cells. The expression of CD147, MMP-2, and MMP-9 mRNAs were determined by real-time quantitative reverse transcription PCR, the levels of cellular surface expression of CD147 were determined by flow cytometry, and the gelatinolytic activity of MMP-2 and MMP-9 were determined by zymography. Our results showed that A771726 significantly inhibited the expression of CD147 on the cell surface of activated THP-1 cells in a dose-dependent manner (P<0.01), inhibited the expression of MMP-2 and MMP-9 mRNAs in a dose-dependent manner (P<0.01), and inhibited the gelatinolytic activity of MMP-2 and MMP-9 at concentration of 15 μg/ml and 45 μg/ml (P<0.01). Our results indicate that A771726, the active metabolite of leflunomide, inhibited CD147 expression at the protein level and inhibited gelatinolytic activity of MMP-2 and MMP-9 in PMA-differentiated THP-1 cells.
最近的研究报告指出，在活动期类风湿关节炎患者外周血 CD14(+)单核细胞中，分化簇（CD）147 的表达升高，并且 CD147 的表达与疾病活动评分相关。因此，CD147 可能是治疗类风湿关节炎的新靶点。来氟米特是一种常用于治疗类风湿关节炎的疾病修饰抗风湿药物。来氟米特阻断 CD147 上调以及阻断活性巨噬细胞中基质金属蛋白酶（MMP）-2 和 MMP-9 下调的作用尚未确定。在这项研究中，我们研究了来氟米特的活性代谢产物 A771726 对佛波醇肉豆蔻酸酯（PMA）分化的 THP-1 细胞中 CD147 表达和 MMP-2 和 MMP-9 明胶酶活性的影响。通过实时定量逆转录 PCR 测定 CD147、MMP-2 和 MMP-9 mRNA 的表达，通过流式细胞术测定细胞表面 CD147 的表达水平，通过明胶酶谱法测定 MMP-2 和 MMP-9 的明胶酶活性。我们的结果表明，A771726 以剂量依赖性方式显著抑制激活的 THP-1 细胞表面 CD147 的表达（P<0.01），以剂量依赖性方式抑制 MMP-2 和 MMP-9 mRNA 的表达（P<0.01），并抑制 MMP-2 和 MMP-9 的明胶酶活性在 15 μg/ml 和 45 μg/ml 浓度下（P<0.01）。我们的结果表明，来氟米特的活性代谢产物 A771726 抑制 PMA 分化的 THP-1 细胞中 CD147 蛋白水平的表达，并抑制 MMP-2 和 MMP-9 的明胶酶活性。
