title: High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine.
abstract: OBJECTIVE
  High mobility group box chromosomal protein 1 (HMGB-1), a nuclear DNA binding protein, was recently rediscovered as a new proinflammatory cytokine. The purpose of this study was to demonstrate HMGB-1 expression in vivo and to identify the role of HMGB-1 in the pathogenesis of rheumatoid arthritis (RA).
  
  
  METHODS
  HMGB-1 concentrations in synovial fluid (SF) and serum from RA and osteoarthritis (OA) patients were measured by immunoblot analysis. The protein's specific receptor, receptor for advanced glycation end products (RAGE), was examined in SF macrophages (SFMs). We measured levels of proinflammatory cytokines released by SFMs treated with HMGB-1 via enzyme-linked immunosorbent assay and used soluble RAGE (sRAGE) to block the release of tumor necrosis factor alpha (TNFalpha). Immunohistochemical analysis and immunofluorescence assay were employed to examine localization of HMGB-1 in RA synovium and its translocation in SFMs after TNFalpha stimulation.
  
  
  RESULTS
  HMGB-1 concentrations were significantly higher in SF of RA patients than in that of OA patients. SFMs expressed RAGE and released TNFalpha, interleukin-1beta (IL-1beta), and IL-6 upon stimulation with HMGB-1. HMGB-1 was found in CD68-positive cells of RA synovium, and TNFalpha stimulation translocated HMGB-1 from the nucleus to the cytosol in SFMs. Blockade by sRAGE inhibited the release of TNFalpha from SFMs.
  
  
  CONCLUSIONS
  HMGB-1 was more strongly expressed in SF of RA patients than in that of OA patients, inducing the release of proinflammatory cytokines from SFMs. HMGB-1 plays a pivotal role in the pathogenesis of RA and may be an original target of therapy as a novel cytokine.
authors.affiliation: Faculty of Medicine, Kagoshima University, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Ko-ichi
authors.initials: K
authors.lastname: Kawahara
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yone
authors.forename: Teruto
authors.initials: T
authors.lastname: Hashiguchi
authors.forename: Munekazu
authors.initials: M
authors.lastname: Yamakuchi
authors.forename: Masamichi
authors.initials: M
authors.lastname: Goto
authors.forename: Keiichi
authors.initials: K
authors.lastname: Inoue
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamada
authors.forename: Kosei
authors.initials: K
authors.lastname: Ijiri
authors.forename: Shunji
authors.initials: S
authors.lastname: Matsunaga
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
authors.forename: Setsuro
authors.initials: S
authors.lastname: Komiya
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013582:Synovial Fluid / Q000166:cytology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha