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

S Nakae, S Saijo, R Horai, K Sudo… - Proceedings of the …, 2003 - National Acad Sciences
S Nakae, S Saijo, R Horai, K Sudo, S Mori, Y Iwakura
Proceedings of the National Academy of Sciences, 2003National Acad Sciences
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-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.
National Acad Sciences