title: Crucial role of the interleukin-6/interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase.
abstract: OBJECTIVE
  To clarify the glucose-6-phosphate isomerase (GPI)-specific CD4+ T cell lineage involved in GPI-induced arthritis and to investigate their pathologic and regulatory roles in the induction of the disease.
  
  
  METHODS
  DBA/1 mice were immunized with GPI to induce arthritis. CD4+ T cells and antigen-presenting cells were cocultured with GPI, and cytokines in the supernatant were analyzed by enzyme-linked immunosorbent assay. Anti-interferon-gamma (anti-IFNgamma) monoclonal antibody (mAb), anti-interleukin-17 (anti-IL-17) mAb, or the murine IL-6 receptor (IL-6R) mAb MR16-1 was injected at different time points, and arthritis development was monitored visually. After MR16-1 was injected, percentages of Th1, Th2, Th17, and Treg cells were analyzed by flow cytometry, and CD4+ T cell proliferation was analyzed using carboxyfluorescein diacetate succinimidyl ester.
  
  
  RESULTS
  GPI-specific CD4+ T cells were found to be differentiated to Th1 and Th17 cells, but not Th2 cells. Administration of anti-IL-17 mAb on day 7 significantly ameliorated arthritis (P < 0.01), whereas administration of anti-IFNgamma mAb exacerbated arthritis. Neither anti-IL-17 mAb nor anti-IFNgamma mAb administration on day 14 ameliorated arthritis. Administration of MR16-1 on day 0 or day 3 protected against arthritis induction, and MR16-1 administration on day 8 significantly ameliorated existing arthritis (P < 0.05). After administration of MR16-1, there was marked suppression of Th17 differentiation, without an increase in Th1, Th2, or Treg cells, and CD4+ T cell proliferation was also suppressed.
  
  
  CONCLUSIONS
  IL-6 and Th17 play an essential role in GPI-induced arthritis. Since it has previously been shown that treatment with a humanized anti-IL-6R mAb has excellent effects in patients with rheumatoid arthritis (RA), we propose that the IL-6/IL-17 axis might also be involved in the generation of RA, especially in the early effector phase.
authors.affiliation: University of Tsukuba, Tsukuba, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Iwanami
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanaka-Watanabe
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mihara
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ohsugi
authors.forename: Mizuko
authors.initials: M
authors.lastname: Mamura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Goto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ito
authors.forename: Akito
authors.initials: A
authors.lastname: Tsutsumi
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005956:Glucose-6-Phosphate Isomerase / Q000009:adverse effects*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D020381:Interleukin-17; D015850:Interleukin-6; D007371:Interferon-gamma; D005956:Glucose-6-Phosphate Isomerase