title: Oleanolic acid acetate inhibits rheumatoid arthritis by modulating T cell immune responses and matrix-degrading enzymes.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jin Kyeong
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, CHA Gumi Medical Center, CHA University, Gumi 730-040, Republic of Korea.
authors.forename: Sung-Wan
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, CHA Gumi Medical Center, CHA University, Gumi 730-040, Republic of Korea.
authors.forename: Duk-Sil
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.
authors.forename: Jong Yeong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea; Bio-Materials Research Institute, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 580-185, Republic of Korea.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Bio-Materials Research Institute, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 580-185, Republic of Korea.
authors.forename: Hyun-Mee
authors.initials: HM
authors.lastname: Oh
authors.affiliation: Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.
authors.forename: Yeong Su
authors.initials: YS
authors.lastname: Ha
authors.affiliation: Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.
authors.forename: Jeongsoo
authors.initials: J
authors.lastname: Yoo
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongbuk 712-749, Republic of Korea.
authors.forename: Pil-Hoon
authors.initials: PH
authors.lastname: Park
authors.affiliation: College of Pharmacy, Woosuk University, Jeonju 565-701, Republic of Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Shin
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.affiliation: Bio-Materials Research Institute, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 580-185, Republic of Korea. Electronic address: rho-m@kribb.re.kr.
authors.forename: Mun-Chual
authors.initials: MC
authors.lastname: Rho
authors.affiliation: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea. Electronic address: shkim72@knu.ac.kr.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000328:Adult; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007660:Ketoprofen / Q000494:pharmacology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014315:Triterpenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D007074:Immunoglobulin G; D016328:NF-kappa B; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; C052658:oleanolic acid 3-acetate; D003907:Dexamethasone; D007660:Ketoprofen; D020928:Mitogen-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse
keywords: Collagen-induced arthritis; Inflammatory cytokine; Lymph nodes; Matrix metalloproteinase; Oleanolic acid acetate; Synovial fibroblasts