Nieminen Riina, Leinonen Sari, Lahti Aleksi, Vuolteenaho Katriina, Jalonen Ulla, Kankaanranta Hannu, Goldring Mary B, Moilanen Eeva
The Immunopharmacology Research Group, Medical School, University of Tampere, and Tampere University Hospital, Research Unit, Finland.
Mediators Inflamm. 2005 Oct 24;2005(5):249-55. doi: 10.1155/MI.2005.249.
Inducible prostaglandin synthase (cyclooxygenase-2, COX-2) is expressed in rheumatoid and osteoarthritic cartilage and produces high amounts of proinflammatory prostanoids in the joint. In the present study we investigated the effects of the inhibitors of mitogen-activated protein kinase (MAPK) pathways Erk1/2, p38, and JNK on COX-2 expression and prostaglandin E2 (PGE2) production in human chondrocytes. Proinflammatory cytokine IL-1beta caused a transient activation of Erk1/2, p38, and JNK in immortalized human T/C28a2 chondrocytes and that was followed by enhanced COX-2 expression and PGE2 production. PD98059 (an inhibitor of Erk1/2 pathway) suppressed IL-1-induced COX-2 expression and PGE2 production in a dose-dependent manner, and seemed to have an inhibitory effect on COX-2 activity. SB203580 (an inhibitor of p38 pathway) but not its negative control compound SB202474 inhibited COX-2 protein and mRNA expression and subsequent PGE2 synthesis at micromolar drug concentrations. SP600125 (a recently developed JNK inhibitor) but not its negative control compound N1-methyl-1,9-pyrazolanthrone downregulated COX-2 expression and PGE2 formation in a dose-dependent manner. SP600125 did not downregulate IL-1-induced COX-2 mRNA expression when measured 2 h after addition of IL-1beta but suppressed mRNA levels in the later time points suggesting post-transcriptional regulation. Our results suggest that activation of Erk1/2, p38, and JNK pathways belongs to the signaling cascades that mediate the upregulation of COX-2 expression and PGE2 production in human chondrocytes exposed to proinflammatory cytokine IL-1beta.
诱导型前列腺素合酶（环氧化酶-2，COX-2）在类风湿性关节炎和骨关节炎软骨中表达，并在关节中产生大量促炎前列腺素。在本研究中，我们研究了丝裂原活化蛋白激酶（MAPK）途径Erk1/2、p38和JNK的抑制剂对人软骨细胞中COX-2表达和前列腺素E2（PGE2）产生的影响。促炎细胞因子IL-1β在永生化人T/C28a2软骨细胞中引起Erk1/2、p38和JNK的瞬时激活，随后COX-2表达和PGE2产生增加。PD98059（Erk1/2途径抑制剂）以剂量依赖性方式抑制IL-1诱导的COX-2表达和PGE2产生，并且似乎对COX-2活性有抑制作用。SB203580（p38途径抑制剂）而非其阴性对照化合物SB202474在微摩尔药物浓度下抑制COX-2蛋白和mRNA表达以及随后的PGE2合成。SP600125（一种最近开发的JNK抑制剂）而非其阴性对照化合物N1-甲基-1,9-吡唑蒽酮以剂量依赖性方式下调COX-2表达和PGE2形成。在添加IL-1β后2小时测量时，SP600125未下调IL-1诱导的COX-2 mRNA表达，但在随后的时间点抑制mRNA水平，提示存在转录后调控。我们的结果表明，Erk1/2、p38和JNK途径的激活属于信号级联反应，介导暴露于促炎细胞因子IL-1β的人软骨细胞中COX-2表达上调和PGE2产生。
