IL-18-deficient mice are resistant to endotoxin-induced liver injury but highly susceptible to endotoxin shock

IL-18 is an IL-1-related cytokine which shares biological functions with IL -12, These include the activation of NK cells, induction of IFN-gamma produ ction and T(h)1 cell differentiation. In this study we analyzed the effect of IL-18 deficiency on lipopolysaccharide (LPS)-induced liver injury and en dotoxin shock in Propionibacterium acnes-primed mice. P.acnes-primed IL-18- deficient (IL-18KO) mice showed resistance to LPS-induced liver injury. Une xpectedly, P. acnes-primed IL-18KO mice were highly susceptible to LPS-indu ced endotoxin shock. Serum level of tumor necrosis factor (TNF)-alpha were markedly elevated (similar to 10-fold higher) within 1.5 h after LPS challe nge in IL-18KO mice as compared with wild-type mice. Anti-TNF-alpha antibod y administration to IL-18KO mice was significantly protective against endot oxin-induced lethality. P. acnes-primed IL-18KO macrophages produced simila r to 6-fold more TNF-alpha protein than did P. acnes-primed wild-type contr ol macrophages. Taken together, these findings demonstrate that ii-is is re sponsible for the progression of endotoxin-induced liver injury as well as down-regulation of endotoxin-induced TNF-alpha production in P. acnes-prime d mice.