Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1β are differentially regulated in human blood mononuclear cells and mouse spleen cells

Interleukin (IL)-18, formerly called interferon gamma (IFN-gamma)-inducing factor, is biologically and structurally related to IL-1 beta. A comparison of gene expression, synthesis, and processing of IL-18 with that of IL-1 beta was made in human peripheral blood mononuclear cells (PBMCs) and in human whole blood. Similar to IL-1 beta, the precursor for IL-18 requires processing by caspase 1. In PBMCs, mature but not precursor IL-18 induces IFN-gamma; in whole human blood stimulated with endotoxin, inhibition of caspase 1 reduces IFN-gamma production by an IL-1 beta-independent mechanism. Unlike the precursor for IL-1 beta, precursor for IL-18 was expressed constitutively in PBMCs and in fresh whole blood from healthy human donors. Western blotting of endotoxin-stimulated PBMCs revealed processed IL-1 beta in the supernatants via an caspase I-dependent pathway. However, in the same supernatants, only unprocessed precursor IL-18 was found. Unexpectedly, precursor IL-18 was found in freshly obtained PBMCs and constitutive IL-18 gene expression was present in whole blood of healthy donors, whereas constitutive IL-1 beta gene expression is absent. Similar to human PBMCs, mouse spleen cells also constitutively contained the preformed precursor for IL-18 and expressed steady-state IL-18 mRNA, but there was no IL-1 beta protein and no spontaneous gene expression for IL-1 beta in these same preparations. We conclude that although IL-18 and IL-1 beta are likely members of the same family, constitutive gene expression, synthesis, and processing are different for the two cytokines.