Interleukin-18 (IFNγ-inducing factor) induces IL-8 and IL-1β via TNFα production from non-CD14+ human blood mononuclear cells

IL-18 is synthesized as a precursor molecule without a signal peptide but requires the IL-1β converting enzyme (ICE, caspase-1) for cleavage into a mature peptide. Human precursor IL-18 was expressed, purified, and cleaved by ICE into a 18-kD mature form. Mature IL-18 induced IL-8, macrophage inflammatory protein-1α, and monocyte chemotactic protein-1 in human peripheral blood mononuclear cells in the absence of any co-stimuli. Blocking IL-1 with IL-1 receptor antagonist resulted in a 50% reduction in IL-8. Neutralization of TNF with TNF binding protein resulted in a 66% reduction in IL-1β, an 80% reduction of IL-8, and an 88% reduction in mean TNFα mRNA. In purified CD14+ cells but not CD3+/CD4+, IL-18 induced gene expression and synthesis of IL-8 and IL-1β. TNFα production was induced in the non-CD14+ population and there was no induction of TNFβ by IL-18. In purified natural killer cells, IL-18 induced IL-8 that was also inhibited by TNF binding protein. IL-18 did not induce antiinflammatory cytokines, IL-1Ra, or IL-10, although IL-18 induction of TNFα was inhibited by IL-10. In the presence of IFNα, IL-18-induced TNFα was enhanced and there was an increase in the mature form of IL-1β. We conclude that IL-18 possesses proinflammatory properties by direct stimulation of gene expression and synthesis of TNFα from CD3+/CD4+ and natural killer cells with subsequent production of IL- 1β and IL-8 from the CD14+ population.