Crucial role of the interleukin-6/interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase
Article first published online: 29 FEB 2008
Copyright © 2008 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 58, Issue 3, pages 754–763, March 2008
How to Cite
Iwanami, K., Matsumoto, I., Tanaka-Watanabe, Y., Inoue, A., Mihara, M., Ohsugi, Y., Mamura, M., Goto, D., Ito, S., Tsutsumi, A., Kishimoto, T. and Sumida, T. (2008), Crucial role of the interleukin-6/interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase. Arthritis & Rheumatism, 58: 754–763. doi: 10.1002/art.23222
- Issue published online: 29 FEB 2008
- Article first published online: 29 FEB 2008
- Manuscript Accepted: 14 NOV 2007
- Manuscript Received: 9 MAY 2007
- Japanese Ministry of Science and Culture
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.
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-γ (anti-IFNγ) 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.
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-IFNγ mAb exacerbated arthritis. Neither anti–IL-17 mAb nor anti-IFNγ 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.
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.