IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist

TLDR

IL‑17 is a T‑cell–derived proinflammatory cytokine elevated in rheumatoid arthritis synovial fluid, yet its pathogenic role in the disease remains unclear. The study examined whether IL‑17 deficiency prevents spontaneous destructive arthritis in IL‑1 receptor antagonist–deficient (IL‑1Ra⁻/⁻) mice. IL‑1 signaling induces OX40 on CD4⁺ T cells, and OX40 cross‑linking amplifies IL‑17 production, placing IL‑17 downstream of IL‑1 via OX40. IL‑17 expression was markedly increased in IL‑1Ra⁻/⁻ mice, and IL‑17 deficiency abolished their spontaneous arthritis and impaired T‑cell activation, demonstrating IL‑17’s essential role downstream of IL‑1 in autoimmune arthritis.

Abstract

IL-17 is a T cell-derived, proinflammatory cytokine that is suspected to be involved in the development of various inflammatory diseases. Although there are elevated levels of IL-17 in synovial fluid of patients with rheumatoid arthritis, the pathogenic role of IL-17 in the development of rheumatoid arthritis remains to be elucidated. In this report, the effects of IL-17 deficiency were examined in IL-1 receptor antagonist-deficient (IL-1Ra −/− ) mice that spontaneously develop an inflammatory and destructive arthritis due to unopposed excess IL-1 signaling. IL-17 expression is greatly enhanced in IL-1Ra −/− mice, suggesting that IL-17 activity is involved in the pathogenesis of arthritis in these mice. Indeed, the spontaneous development of arthritis did not occur in IL-1Ra −/− mice also deficient in IL-17. The proliferative response of ovalbumin-specific T cells from DO11.10 mice against ovalbumin cocultured with antigen-presenting cells from either IL-1Ra −/− mice or wild-type mice was reduced by IL-17 deficiency, indicating insufficient T cell activation. Cross-linking OX40, a cosignaling molecule on CD4 + T cells that plays an important role in T cell antigen-presenting cell interaction, with anti-OX40 Ab accelerated the production of IL-17 induced by CD3 stimulation. Because OX40 is induced by IL-1 signaling, IL-17 induction is likely to be downstream of IL-1 through activation of OX40. These observations suggest that IL-17 plays a crucial role in T cell activation, downstream of IL-1, causing the development of autoimmune arthritis.