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-1 beta 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-1 alpha, 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-1 beta, an 80% reduction of IL-8, and an 88% reduction in mean TNF alpha mRNA, In purified CD14(+) cells but not CD3(+)/CD4(+), IL-18 induced gene expression and synthesis of IL-8 and IL-1 beta, TNF alpha production was induced in the non-CD14(+) population and there was no induction of TNF beta 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 TNF alpha was inhibited by IL-10, In the presence of IFN gamma, IL-18-induced TNF alpha was enhanced and there was an increase in the mature form of IL-1 beta, We conclude that IL-18 possesses proinflammatory properties by direct stimulation of gene expression and synthesis of TNF alpha from CD3(+)/CD4(+) and natural killer cells with subsequent production of IL-1 beta and IL-8 from the CD14(+) population.