Choi Jin Kyeong, Kim Sung-Wan, Kim Duk-Sil, Lee Jong Yeong, Lee Soyoung, Oh Hyun-Mee, Ha Yeong Su, Yoo Jeongsoo, Park Pil-Hoon, Shin Tae-Yong, Kwon Taeg Kyu, Rho Mun-Chual, Kim Sang-Hyun
Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea; Molecular Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Thoracic and Cardiovascular Surgery, CHA Gumi Medical Center, CHA University, Gumi 730-040, Republic of Korea.
Toxicol Appl Pharmacol. 2016 Jan 1;290:1-9. doi: 10.1016/j.taap.2015.11.005. Epub 2015 Nov 10.
Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with a combination of synovium joint inflammation, synovium hyperplasia, and destruction of cartilage and bone. Oleanolic acid acetate (OAA), a compound isolated from Vigna angularis, has been known to possess pharmacological activities, including anti-inflammation and anti-bone destruction. In this study, we investigated the effects of OAA on RA and the underlying mechanisms of action by using a type-II collagen-induced arthritis (CIA) mouse model and tumor necrosis factor (TNF)-α-stimulated RA synovial fibroblasts. Oral administration of OAA decreased the clinical arthritis symptoms, paw thickness, histologic and radiologic changes, and serum total and anti-type II collagen IgG, IgG1, and IgG2a levels. OAA administration reduced Th1/Th17 phenotype CD4(+) T lymphocyte expansions and inflammatory cytokine productions in T cell activated draining lymph nodes and spleen. OAA reduced the expression and production of inflammatory mediators, such as cytokines and matrix metalloproteinase (MMP)-1/3, in the ankle joint tissue and RA synovial fibroblasts by down-regulating Akt, mitogen-activated protein kinases, and nuclear factor-κB. Our results clearly support that OAA plays a therapeutic role in RA pathogenesis by modulating helper T cell immune responses and matrix-degrading enzymes. The immunosuppressive effects of OAA were comparable to dexamethasone and ketoprofen. We provide evidences that OAA could be a potential therapeutic candidate for RA.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，与滑膜关节炎症、滑膜增生以及软骨和骨破坏相关。醋酸齐墩果酸（OAA）是从赤小豆中分离出的一种化合物，已知具有多种药理活性，包括抗炎和抗骨破坏作用。在本研究中，我们通过使用II型胶原诱导的关节炎（CIA）小鼠模型和肿瘤坏死因子（TNF）-α刺激的RA滑膜成纤维细胞，研究了OAA对RA的影响及其潜在作用机制。口服OAA可减轻临床关节炎症状、爪厚度、组织学和放射学变化，以及血清总抗II型胶原IgG、IgG1和IgG2a水平。给予OAA可减少T细胞活化的引流淋巴结和脾脏中Th1/Th17表型CD4(+)T淋巴细胞扩增和炎性细胞因子产生。OAA通过下调Akt、丝裂原活化蛋白激酶和核因子-κB，降低踝关节组织和RA滑膜成纤维细胞中炎性介质如细胞因子和基质金属蛋白酶（MMP）-1/3的表达和产生。我们的结果明确支持OAA通过调节辅助性T细胞免疫反应和基质降解酶在RA发病机制中发挥治疗作用。OAA的免疫抑制作用与地塞米松和酮洛芬相当。我们提供的证据表明，OAA可能是RA的一种潜在治疗候选药物。
