Role of interleukin-18 (IL-18) during lethal shock: Decreased lipopolysaccharide sensitivity but normal superantigen reaction in IL-18-deficient mice

Lethal shock can be associated with excessive secretion of cytokines such a s tumor necrosis factor (TNF) and gamma interferon (IFN-gamma), IFN-gamma m ediates macrophage activation and appears to be controlled by interleukin ( IL)-12 and IL-18. To investigate the role of IL-18 in vivo, we generated IL -18-deficient mice by gene targeting. IL-18(-/-) mice showed decreased sens itivity towards lipopolysaccharide (LPS)-induced shock LPS-induced IFN-gamm a production was abrogated, yet induction of IL-12 and TNF was not affected . Both wild-type and IL-18-deficient mice succumbed to LPS-induced lethal s hock after sensitization with D-galactosamine. However, in marked contrast to LPS, the bacterial superantigen Staphylococcus aureus enterotoxin B (SEB ) induced comparable serum levels of IFN-gamma in IL-18(+/+) and IL-18(-/-) mice, accompanied by an upregulation of cell surface markers CD14, CD122 ( IL-2R beta), and CD132 (IL-2R gamma) on peritoneal macrophages. Moreover, S EB injection rendered IL-18-deficient mice sensitive for subsequent challen ge with LPS, The degree of sensitization was comparable to that in wild-typ e controls with respect to lethality, However, LPS-induced TNF levels in se rum were significantly reduced in SEB-sensitized IL-18-deficient mice, Thes e results imply that IL-18 plays an important role in induction of IFN-gamm a and lethality in response to LPS.