INTERLEUKIN-18 (IFN-GAMMA-INDUCING FACTOR) INDUCES IL-8 AND IL-1-BETAVIA TNF-ALPHA PRODUCTION FROM NON-CD14(-CELLS() HUMAN BLOOD MONONUCLEAR)

IL-18 is synthesized as a precursor molecule without a signal peptide but requires the IL-1 beta converting enzyme (ICE, caspase-1) for clea vage into a mature peptide, Human precursor IL-18 was expressed, purif ied, and cleaved by ICE into a 18-kD mature form, Mature IL-18 induced IL-8, macrophage inflammatory protein-1 alpha, and monocyte chemotact ic protein-1 in human peripheral blood mononuclear cells in the absenc e of any co-stimuli, Blocking IL-1 with IL-1 receptor antagonist resul ted 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 synth esis of IL-8 and IL-1 beta, TNF alpha production was induced in the no n-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 inh ibited by TNF binding protein, IL-18 did not induce antiinflammatory c ytokines, 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 al pha was enhanced and there was an increase in the mature form of IL-1 beta, We conclude that IL-18 possesses proinflammatory properties by d irect stimulation of gene expression and synthesis of TNF alpha from C D3(+)/CD4(+) and natural killer cells with subsequent production of IL -1 beta and IL-8 from the CD14(+) population.