Aizman E, Blacher E, Ben-Moshe O, Kogan T, Kloog Y, Mor A
Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel.
Clin Exp Immunol. 2014 Mar;175(3):458-67. doi: 10.1111/cei.12235.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by pronounced inflammation and leucocyte infiltration in affected joints. Despite significant therapeutic advances, a new targeted approach is needed. Our objective in this work was to investigate the anti-inflammatory effects of the Ras inhibitor farnesylthiosalicylic acid (FTS) on adjuvant-induced arthritis (AIA) in rats, an experimental model for RA. Following AIA induction in Lewis rats by intradermal injection of heat-killed Mycobacterium tuberculosis, rats were treated with either FTS or dexamethasone and assessed daily for paw swelling. Joints were imaged by magnetic resonance imaging and computerized tomography and analysed histologically. The anti-inflammatory effect of FTS was assessed by serum assay of multiple cytokines. After adjuvant injection rats demonstrated paw swelling, leucocyte infiltration, cytokine secretion and activation of Ras-effector pathways. Upon FTS treatment these changes reverted almost to normal. Histopathological analysis revealed that the synovial hyperplasia and leucocyte infiltration observed in the arthritic rats were alleviated by FTS. Periarticular bony erosions were averted. Efficacy of FTS treatment was also demonstrated by inhibition of CD4(+) and CD8(+) T cell proliferation and of interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-17 release. The Ras effectors PI3K, protein kinase B (AKT), p38, and extracellular-regulated kinase (ERK) were significantly attenuated and forkhead box protein 3 (FoxP3) transcription factor, a marker of regulatory T cells, was significantly increased. Thus, FTS possesses significant anti-inflammatory and anti-arthritic properties and accordingly shows promise as a potential therapeutic agent for RA. Its effects are apparently mediated, at least in part, by a decrease in proinflammatory cytokines.
类风湿性关节炎（RA）是一种自身免疫性疾病，其特征是受累关节出现明显炎症和白细胞浸润。尽管在治疗方面取得了重大进展，但仍需要一种新的靶向治疗方法。我们在这项研究中的目的是研究Ras抑制剂法尼基硫代水杨酸（FTS）对佐剂性关节炎（AIA）大鼠（一种RA实验模型）的抗炎作用。通过皮内注射热灭活的结核分枝杆菌在Lewis大鼠中诱导AIA后，将大鼠用FTS或地塞米松治疗，并每天评估爪肿胀情况。通过磁共振成像和计算机断层扫描对关节进行成像，并进行组织学分析。通过多种细胞因子的血清检测评估FTS的抗炎作用。佐剂注射后，大鼠出现爪肿胀、白细胞浸润、细胞因子分泌和Ras效应途径的激活。FTS治疗后，这些变化几乎恢复正常。组织病理学分析显示，FTS减轻了关节炎大鼠中观察到的滑膜增生和白细胞浸润。避免了关节周围骨质侵蚀。FTS治疗的有效性还通过抑制CD4(+)和CD8(+) T细胞增殖以及干扰素（IFN）-γ、肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6和IL-17的释放得到证明。Ras效应器PI3K、蛋白激酶B（AKT）、p38和细胞外调节激酶（ERK）显著减弱，而调节性T细胞标志物叉头框蛋白3（FoxP3）转录因子显著增加。因此，FTS具有显著的抗炎和抗关节炎特性，因此有望成为RA的潜在治疗药物。其作用显然至少部分是由促炎细胞因子的减少介导的。
