Combined effects of IL-12 and IL-18 on the induction of collagen-induced arthritis

IL-18 expression has recently been detected in rheumatoid arthritis (RA) sy novial membrane. We investigated the mechanisms by which IL-18-induced coll agen-induced arthritis in DBA/1 mice primed intradermally with type II bovi ne collagen in IFA and boosted i.p. 21 days later with CII in saline. Mice were injected i.p. with rIL-12, rIL-18, or both (100 ng) during days -1 to 4 and again on days 20-24, Control mice received PBS. Mice treated with IL- 12 or IL-18 alone developed significantly higher incidence and more severe disease compared with controls. These were elevated further by combination treatment with IL-12 and IL-18, The cytokine treatments led to markedly enh anced synovial hyperplasia, cellular infiltration, and cartilage erosion co mpared with controls, Cytokine-treated mice produced significantly more IFN -gamma, TNF-alpha and IL-6 than the controls. Interestingly, IL-18-treated mice produced more TNF-alpha and IL-6, but less IFN-gamma, compared with mi ce treated with IL-12, Furthermore, splenic macrophages from DBA/1 mice cul tured in vitro with IL-18, but not IL-12, produced substantial amounts of T NF-alpha, Mice treated with IL-18 or IL-18 plus IL-12 produced markedly mor e IgG1 and IgG2a anti-collagen Ab compared with controls, whereas IL-12 tre atment only led to an enhanced IgG2a response. Together these results demon strate that IL-18 can promote collagen-induced inflammatory arthritis throu gh mechanisms that may be distinct from those induced by IL-12.