Interleukin-18 induces production of proinflammatory cytokines in mice: no intermediate role for the cytokines of the tumor necrosis factor family and interleukin-1β

Abstract

Interleukin‐18 (IL‐18) is not only a co‐stimulus for the induction of interferon‐γ but also has direct proinflammatory effects by inducing tumor necrosis factor‐α (TNF‐α), IL‐1β, IL‐8 and IL‐6. However, the cascade 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 of second‐wave cytokines such as IL‐6 by IL‐18 is driven by intermediary induction of endogenous cytokines of the TNF family or IL‐1β. When mouse peritoneal macrophages were stimulated in vitro with recombinant murine IL‐18, there was a dose‐dependent induction of TNF, IL‐1α, and IL‐1β. IL‐6 synthesis was also strongly induced by IL‐18 and, as revealed by studies in knockout mice, this production was not dependent on interactions between endogenous cytokines of the TNF/TNF receptor family: TNF‐α, lymphotoxin‐α, Fas/Fas ligand (L) or CD40/CD40L. Moreover, the induction of IL‐6 was also independent of endogenous IL‐1β, as macrophages isolated from IL‐1β deficient mice produced normal amounts of IL‐6 after stimulation with IL‐18. In conclusion, murine IL‐18 has pleiotropic proinflammatory activities by inducing production of TNF‐α, IL‐1α, IL‐1β and IL‐6, which could have important consequences for the pathophysiology of infectious and autoimmune diseases.