title: Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications.
abstract: OBJECTIVE
  Semaphorin 4D (Sema4D)/CD100 has pleiotropic roles in immune activation, angiogenesis, bone metabolism, and neural development. We undertook this study to investigate the role of Sema4D in rheumatoid arthritis (RA).
  
  
  METHODS
  Soluble Sema4D (sSema4D) levels in serum and synovial fluid were analyzed by enzyme-linked immunosorbent assay. Cell surface expression and transcripts of Sema4D were analyzed in peripheral blood cells from RA patients, and immunohistochemical staining of Sema4D was performed in RA synovium. Generation of sSema4D was evaluated in an ADAMTS-4-treated monocytic cell line (THP-1 cells). The efficacy of anti-Sema4D antibody was evaluated in mice with collagen-induced arthritis (CIA).
  
  
  RESULTS
  Levels of sSema4D were elevated in both serum and synovial fluid from RA patients, and disease activity markers were correlated with serum sSema4D levels. Sema4D-expressing cells also accumulated in RA synovium. Cell surface levels of Sema4D on CD3+ and CD14+ cells from RA patients were reduced, although levels of Sema4D transcripts were unchanged. In addition, ADAMTS-4 cleaved cell surface Sema4D to generate sSema4D in THP-1 cells. Soluble Sema4D induced tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) production from CD14+ monocytes. IL-6 and TNFα induced ADAMTS-4 expression in synovial cells. Treatment with an anti-Sema4D antibody suppressed arthritis and reduced proinflammatory cytokine production in CIA.
  
  
  CONCLUSIONS
  A positive feedback loop involving sSema4D/IL-6 and TNFα/ADAMTS-4 may contribute to the pathogenesis of RA. The inhibition of arthritis by anti-Sema4D antibody suggests that Sema4D represents a potential therapeutic target for RA.
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogata
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Sujin
authors.initials: S
authors.lastname: Kang
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Ebina
authors.affiliation: Osaka University Graduate School of Medicine and Osaka University Hospital, Osaka, Japan.
authors.forename: Kenrin
authors.initials: K
authors.lastname: Shi
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nojima
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Morimoto
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nishide
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hosokawa
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Shima
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Narazaki
authors.affiliation: National Hospital Organization Osaka Minami Medical Center, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tsuboi
authors.affiliation: National Hospital Organization Osaka Minami Medical Center, Osaka, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Saeki
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
mesh_terms: D051722:ADAM Proteins / Q000276:immunology; D000071121:ADAMTS4 Protein; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D001169:Arthritis, Experimental; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D016207:Cytokines; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D018836:Inflammation Mediators; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D011348:Procollagen N-Endopeptidase / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D039961:Semaphorins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D013582:Synovial Fluid / Q000737:chemistry; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C093224:CD100 antigen; D016207:Cytokines; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D012333:RNA, Messenger; D039961:Semaphorins; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C000603919:Adamts4 protein, mouse