Interleukin-18 regulation of interferon γ production and cell proliferation as shown in interleukin-1β-converting enzyme (Caspase-1)-deficient mice

Interleukin-18 (IL-18) is a costimulatory factor for interferon gamma (IFN gamma) production. Processing of pro-IL-18 by IL-1 beta-converting enzyme (ICE) leads to the release of bioactive IL-18. Compared with wild-type (WT) mice, splenocytes from ICE-deficient mice produced low IFN gamma after lipopolysaccharide (LPS) or zymosan (50% and 80% reduction). In contrast, IFN gamma production was unimpaired in ICE-deficient mice using Concanavalin A (Con A). Comparable results were obtained when endogenous IL-18 was blocked with a neutralizing antibody, LPS-induced IFN gamma was also reduced by an ICE inhibitor. Exogenous IL-18 augmented zymosan-induced IFN gamma production in WT mice. In ICE-deficient cells, IFN gamma production was only partially restored by IL-18. The reduced levels of IFN gamma in ICE-deficient mice were not due to a lack of IL-12, because zymosan induced IL-12 equally in WT and in ICE-deficient mice. IFN gamma is an important regulator of cell proliferation. In accordance, splenocytes from ICE-deficient mice proliferated more when stimulated with LPS, but not with Con A. Furthermore, in ovalbumin-sensitized ICE-deficient mice, proliferation of lymph node cells in response to the specific antigen was not altered, Exogenous IFN gamma inhibited, whereas blockade of endogenous IFN gamma or IL-18 increased, LPS induced splenocyte proliferation both in WT and in ICE-deficient mice. Our results show that IL-18 is an IL-12-independent regulator of IFN gamma production and of cell proliferation induced by microbial stimuli, However, ICE-dependent processing of IL-18 is not needed for response to mitogens or antigens. (C) 1998 by The American Society of Hematology.