title: Chemically modified ribozyme targeting TNF-alpha mRNA regulates TNF-alpha and IL-6 synthesis in synovial fibroblasts of patients with rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is chronic polyarthritis in which a variety of inflammatory cytokines play a role. Since tumor necrosis factor-alpha (TNF-alpha) is one of the most important cytokines in the pathogenesis of RA, we evaluated the feasibility of ribozymes as a therapeutic agent to control the inflammatory process of RA synovium. A hammerhead ribozyme against TNF-alpha was chemically modified to increase nuclease resistance and added to RA fibroblastlike cell cultures without using a delivery system. The cellular uptake of fluorescent-labeled ribozyme into synovial cells was found to last at least 48 hr by confocal laser scanning microscopy. The ribozyme targeting TNF-alpha gene inhibited both the expression of TNF-alpha mRNA and the secretion of TNF-alpha and IL-6. The cytotoxic effect by the ribozyme on synovial cells was negligible when determined by an alamar blue assay. Chemically modified ribozymes designed to suppress the TNF-alpha gene may be potential as a therapeutic agent for rheumatoid arthritis.
authors.affiliation: Department of Clinical Medicine, Tohoku University, School of Medicine, Sendai, Japan. minakot@mail.cc.tohoku.ac.jp
authors.forename: Minako
authors.initials: M
authors.lastname: Takahashi
authors.forename: Tadao
authors.initials: T
authors.lastname: Funato
authors.forename: Yoko
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujii
authors.forename: Keiko Kumura
authors.initials: KK
authors.lastname: Ishii
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kaku
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sasaki
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D001483:Base Sequence; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000096:biosynthesis*; D016337:RNA, Catalytic / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D015850:Interleukin-6; D016337:RNA, Catalytic; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha