Interleukin-18 induces production of proinflammatory cytokines in mice: nointermediate role for the cytokines of the tumor necrosis factor family and interleukin-1 beta

Interleukin-18 (IL-18) is not only a co-stimulus for the induction of inter feron-gamma but also has direct proinflammatory effects by inducing tumor n ecrosis factor-alpha (TNF-alpha), IL-1 beta, IL-8 and IL-6. However, the ca scade of events leading to induction of cytokines by IL-18 is unclear. The aim of the present study was to investigate whether murine IL-18 stimulates production of proinflammatory cytokines, and to assess whether induction o f second-wave cytokines such as IL-6 by IL-18 is driven by intermediary ind uction of endogenous cytokines of the TNF family or IL-1 beta. When mouse p eritoneal macrophages were stimulated in vitro with recombinant murine IL-1 8, there was a dose-dependent induction of TNF, IL-1 alpha, and IL-1 beta. IL-6 synthesis was also strongly induced by IL-18 and, as revealed by studi es in knockout mice, this production was not dependent on interactions betw een endogenous cytokines of the TNF/TNF receptor family: TNF-alpha, lymphot oxin-alpha, Fas/Fas ligand (L) or CD40/CD40L. Moreover, the induction of IL -6 was also independent of endogenous IL-1 beta, as macrophages isolated fr om IL-1 beta deficient mice produced normal amounts of IL-6 after stimulati on with IL-18. In conclusion, murine IL-18 has pleiotropic proinflammatory activities by inducing production of TNF-alpha, IL-1 alpha, IL-1 beta and I L-6, which could have important consequences for the pathophysiology of inf ectious and autoimmune diseases.