title: Effect of nuclear factor-kappaB inhibition on rheumatoid fibroblast-like synoviocytes and collagen induced arthritis.
abstract: OBJECTIVE
  The nuclear factor-kB (NF-kB) signaling pathway has been implicated as a molecular target for the treatment of various inflammatory diseases, such as rheumatoid arthritis (RA). In particular, IkB kinase (IKK) is considered an important molecular target because the majority of inflammatory signaling pathways mediated by NF-kB involve IKK activation. We investigated the effect of NF-kB inhibition on rheumatoid fibroblast-like synoviocytes (FLS) and collagen induced arthritis.
  
  
  METHODS
  We evaluated the effect of IMD-0560, an inhibitor of IKK, on rheumatoid FLS in vitro and on collagen type II induced arthritis in mice.
  
  
  RESULTS
  IMD-0560 suppressed the nuclear translocation of NF-kB and phosphorylation of IkBa induced by tumor necrosis factor-a in FLS. In addition, this compound suppressed the production of inflammatory cytokines, including interleukin 6 (IL-6), IL-8, and monocyte chemoattractant protein-1. IMD-0560 also inhibited the proliferation of FLS without showing cellular toxicity. Finally, this compound was effective against collagen induced arthritis in mice.
  
  
  CONCLUSIONS
  Based on these results, IMD-0560 could be a new therapeutic agent for RA.
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Japan. okazaki@tkf.att.ne.jp
authors.forename: Yuko
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Sawada
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nagatani
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Komagata
authors.forename: Tetsufumi
authors.initials: T
authors.lastname: Inoue
authors.forename: Susumu
authors.initials: S
authors.lastname: Muto
authors.forename: Akiko
authors.initials: A
authors.lastname: Itai
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects*
chemical_list: D001549:Benzamides; D016207:Cytokines; D020672:I-kappa B Proteins; C503742:N-(2,5-bis(trifluoromethyl)phenyl)-5-bromo-2-hydroxybenzamide; D016328:NF-kappa B