Reduced incidence and severity of collagen-induced arthritis in mice lacking IL-18

We have recently reported the presence and a potential proinflammatory role of IL-18 in the synovium of patients with rheumatoid arthritis, To obtain direct evidence that IL-18 plays an influential role in articular inflammat ion, we investigated the development of collagen-induced arthritis in a str ain of mice lacking IL-18 (IL-18(-/-)) of DBA/1 background. IL-18(-/-) mice developed markedly reduced incidence of arthritis compared with heterozygo us or wild-type mice. Of the IL-18(-/-) mice that developed arthritis, the severity of the disease was significantly reduced compared with the intact mice, This was accompanied by reduced articular inflammation and destructio n evident on histology, IL-18(-/-) mice also had significantly reduced Ag-s pecific proliferation and proinflammatory cytokine (IFN-gamma, TNF-alpha, I L-6, and IL-12) production by spleen and lymph node cells in response to bo vine type II collagen (CII) in vitro compared with wild-type mice, parallel ed in vivo by a significant reduction in serum anti-CII IgG2a Ab level. Tre atment with rIL-18 completely reversed the disease of the IL-18(-/-) mice t o that of the wild-type mice, These data directly demonstrate a pivotal rol e of IL-18 in the development of inflammatory arthritis and suggest that an tagonists to IL-18 may have therapeutic potential in rheumatic diseases.