Local inhibition of endogenous IL-18 through adenoviral overexpression of IL-18BPc results in reduced incidence and severity of collagen induced arthritis in mice

IL-18 is a member of the interleukin-1 family and plays an important role in innate and acquired immunity. Previous experiments focused on IL-18 in experimental arthritis showed that neutralization through systemic treatment with either antibodies or IL-18 binding protein (IL-18BP) ameliorated the disease. To study the local role of IL-18 in arthritis we developed a replication deficient adenoviral vector containing the murine IL-18BP isoform c gene (Ad5CMV.IL-18BPc). The neutralizing ability of adenoviral overexpressed IL-18BPc on IL-18 response was tested in vitro. Supernatants of IL-18BP transfected cells significantly inhibited IL-18 induced luciferase production in IL-18 sensitive NFkB luciferase reporter fibroblasts. Next we injected 1 × 107PFU of Ad5CMV.IL-18BPc or the control vector Ad5CMV.Luc into the murine knee joint cavity of DBA/1 mice before onset of collagen-induced arthritis (CIA). IL-18BPc overexpression significantly reduced local knee joint swelling in CIA with 66% (P < 0.001) and distal paw swelling with approx. 50% (P < 0.01) compared to the control vector. Furthermore, local IL-18BPc resulted in lower serum levels of IL-6 compared to the control (respectively 5.0 pg/ml and 12.7 pg/ml, P < 0.001). Serum titers of specific IgG1, IgG2a and total IgG antibodies directed towards collagen type II showed no significant differences between control and IL-18BPc treatment, indicating that the effect seen on arthritis by overexpression of IL-18BPc in the joint was not caused by an IL-18BPc effect on humoral immunity. These results clearly show that IL-18 present in the arthritic joint plays an important proinflammatory role and demonstrate that adenoviral overexpression of IL-18BPc in the synovium is an efficacious local treatment in experimental arthritis.