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Functional Reconstitution and Regulation of IL-18 Activity by the IL-18Rβ Chain1

IL-18 and IL-12 are major IFN-γ-inducing cytokines but the unique synergism of IL-18 and IL-12 remains unclear. In the human NK cell line NKO, IL-18Rα, and IL-18Rβ are expressed constitutively but IL-18 did not induce IFN-γ unless IL-12 was present. COS-1 fibroblasts, which produce the chemokine IL-8 when stimulated by IL-1β or TNF-α, do not respond to IL-18, despite abundant expression of the IL-18Rα chain. COS-1 cells lack expression of the IL-18Rβ chain. The IL-18Rβ cDNA was cloned from a human T-B lymphoblast cDNA library and COS-1 cells were transiently transfected with the IL-18Rβ chain and a luciferase reporter. In transfected COS-1 cells, IL-18 induced IL-8 and luciferase in the absence of IL-12 and independently of IL-1 and TNF. Ab against the IL-18Rα chain, however, prevented IL-18 responsiveness in COS-1 cells transfected with the IL-18Rβ chain, suggesting that both chains be functional. In NKO cells and PBMC, IL-12 increased steady-state mRNA levels of IL-18Rα and IL-18Rβ; the production of IFN-γ corresponded to IL-12-induced IL-18Rα and IL-18Rβ chains. We conclude that functional reconstitution of the IL-18Rβ chain is essential for IL-12-independent proinflammatory activity of IL-18-induced IL-8 in fibroblasts. The synergism of IL-18 plus IL-12 for IFN-γ production is, in part, due to IL-12 up-regulation of both IL-18Rα and IL-18Rβ chains, although postreceptor events likely contribute to IFN-γ production.