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-␥ (anti-IFN␥) 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-IFN␥ mAb exacerbated arthritis.Neither anti-IL-17 mAb nor anti-IFN␥ 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.Conclusion. 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.

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism

“…Anti-IL-6R therapy is widely used to treat rheumatoid arthritis because of its strong anti-inflammatory effect [18,39,40]. Previous studies reported an effect of MR16-1 or tocilizumab on the Treg count [41,42], although other studies did not show any effect [43,44]. In our study, cytokine concentrations were not markedly increased in plasma from mSOD1 mice, except for CXCL1 (KC).…”

Interleukin‐6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses

“…A clear limitation of MR16-1 (rat IgG1) compared with TNFR-Fc in CIA is that repeated injection of this antibody in mice is not possible because it induces an anaphylactoid reaction (Mihara M, et al: unpublished observations). However, in a previous study of glucose-6-phosphate isomeraseinduced arthritis, another model of human RA, a single administration of MR16-1 either before or after disease onset showed protective efficacy (24), suggesting an effect of MR16-1 that is distinct from that on T helper cell differentiation. Nevertheless, the results of the present study suggest that the modulation of T helper responses, and particularly the inhibition of Th17 cell development, by the early administration of MR16-1 is the key protective mechanism for the observed inhibition of CIA.…”

Interleukin‐6 Receptor Blockade Enhances CD39+ Regulatory T Cell Development in Rheumatoid Arthritis and in Experimental Arthritis

“…Studies in various autoimmunity models, such as experimental autoimmune encephalomyelitis (36), uveoretinitis (37), CIA (2,38), and glucose-6-phosphate isomerase-induced arthritis (39), showed that anti-IL-6R antibody treatment suppressed antigen-specific Th17 cell differentiation. In our study, Th17 cell frequencies were not significantly different between tocilizumab responders and nonresponders, and no significant changes were observed throughout the course of CIA in MR16-1-treated mice.…”