New therapeutic approach for rheumatoid arthritis by targeting the intracellular molecule.

我们发现，一些传统的非甾体抗炎药（NSAID），如吲哚美辛和双氯芬酸诱导类风湿性滑膜成纤维细胞凋亡（J Pharmacol Exp Ther 2002;302：18）。我们还发现，选择性环氧合酶（考克斯）-2抑制剂塞来昔布通过COX非依赖性机制对类风湿性滑膜成纤维细胞（Arthritis Rheum 2002;46：3159）和结肠癌细胞系（FEBS Lett 2002;531：278）发挥促凋亡作用。此外，高浓度的阿司匹林和水杨酸盐（J Pharm Pharmacol 2002;54：1675）和雷公藤内酯醇（一种在传统中药中鉴定的活性化合物）（BMC Pharmacol 2002;4：2）诱导类风湿性滑膜细胞凋亡。从这些发现，我们推测，一些细胞内的分子发挥重要作用，诱导凋亡的抗炎药物。在研究过程中，我们发明了一种新的有效的促凋亡剂来自塞来昔布。我们现在正试图找到靶向分子， ...更多信息 诱导细胞凋亡。关于花生四烯酸级联反应，最近的研究表明，不仅考克斯，而且末端酶如前列腺素E合成酶（PGES）在理解炎症的发病机制和NSAIDs的作用机制中也是重要的。PGES是最近鉴定的末端酶，其作用于考克斯的下游并催化前列腺素（PG）H2转化为PGE 2。目前已克隆到的PGES同工酶至少有三种，分别为膜结合型PGES（mPGES）-1、mPGES-2和胞质型PGES。mPGES-1在类风湿性关节炎和骨关节炎患者的关节组织组分中的诱导已经由我们在体外证实（J Rheumatol 2002;29：1836 & Arthritis Res Ther 2004;6：R355）。然后，我们表明PGE 2是类风湿性滑膜成纤维细胞中白介素-16诱导的mPGES-1表达的增强剂（Arthritis Rheum 2003;48：2819）。这些结果表明，mPGES-1可能是一个新的治疗关节炎的目标。PGD合酶（PGDS）是一种产生内在促凋亡PG（15-脱氧-Δ β <12，14>-PGJ 2）的酶。我们还在动物模型中发现了逆转录病毒转染的表达PGDS的成纤维细胞在博来霉素诱导的肺损伤（Am J Respir Cell Mol Biol 2003;28：582）和尿酸盐一水合物晶体诱导的急性炎症（Arthritis Rheum 2003;48：2931）中的抗炎作用。PGDS或15-脱氧-Δ^<12，14>-PGJ 2可能成为类风湿性关节炎和其他风湿性疾病新疗法的另一个靶分子。少

We found that some conventional nonsteroidal anti-inflammatory drugs(NSAIDs) such as indometacin and diclofenac induced apoptosis in rheumatoid synovial fibroblasts (J Pharmacol Exp Ther 2002;302:18). We also found that celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, exert pro-apoptotic effect on rheumatoid synovial fibroblasts (Arthritis Rheum 2002;46:3159) and colon cancer cell lines (FEBS Lett 2002;531:278) by COX-independent mechanisms. In addition, high concentration of aspirin and salicylate (J Pharm Pharmacol 2002;54:1675), and triptolide, an active compound identified in a traditional Chinese herb (BMC Pharmacol 2002;4:2), induce apoptosis in rheumatoid synovial cells. From these finding, we hypothesized that some intracellular molecules play an important role in inducing apoptosis by these anti-inflammatory agents. During the research procedure, we invented a novel potent pro-apoptotic agent derived from celecoxib. We are now trying to find the targeting molecule to i … More nduce apoptosis. Concerning arachidonic acid cascade, recent studies revealed that not only COX but also terminal enzymes such as prostaglandin E synthase(PGES) are important in the understanding of the pathogenesis of inflammation and mechanisms of action of NSAIDs. PGES is a recently identified terminal enzyme that acts downstream of COX and catalyzes the conversion of prostaglandin(PG) H2 to PGE2. At least three isozymes have been cloned so far, which are called membrane-associated PGES(mPGES)-1,mPGES-2,and cytosolic PGES. Induction of mPGES-1 in the component of articular tissues of patients with rheumatoid arthritis and osteoarthritis has been demonstrated in vitro by us (J Rheumatol 2002;29:1836 & Arthritis Res Ther 2004;6:R355). We then showed that PGE2 is an enhancer for interleukin-16-induced expression of mPGES-1 in rheumatoid synovial fibroblasts (Arthritis Rheum 2003;48:2819). These findings suggest that mPGES-1 may be a novel therapeutic target for arthritis. PGD synthase(PGDS) is an enzyme to produce an intrinsic pro-apoptotic PG (15-deoxy-Δ^<12,14>-PGJ2). We also found the anti-inflammatory effects of the retrovirally transfected PGDS-expressing fibroblasts in bleomycin-induced lung injury (Am J Respir Cell Mol Biol 2003;28:582) and monosodium urate monohydrate crystal-induced acute inflammation (Arthritis Rheum 2003;48:2931) in animal models. PGDS or 15-deoxy-Δ^<12,14>-PGJ2 will possibly be another target molecule for the novel therapy for rheumatoid arthritis and other rheumatic diseases. Less