Human Blood Mononuclear Cells

IL-18 is synthesized as a precursor molecule without a signal peptide but requires the IL-1 b 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 a , 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 b , an 80% reduction of IL-8, and an 88% reduction in mean TNF a mRNA. In purified CD14 1 cells but not CD3 1 /CD4 1 , IL-18 induced gene expression and synthesis of IL-8 and IL-1 b . TNF a production was induced in the non-CD14 1 population and there was no induction of TNF b 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 a was inhibited by IL-10. In the presence of IFN g , IL-18–induced TNF a was enhanced and there was an increase in the mature form of IL-1 b . We conclude that IL-18 possesses proinflammatory properties by direct stimulation of gene expression and synthesis of TNF a from CD3 1 /CD4 1 and natural killer cells with subsequent production of IL-1 b and IL-8 from the CD14 1 population. ( J. Clin. Invest. 1998. 101:711– 721.)