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 production and Th1 cell differentiation. In this study we analyzed the effect of IL-18 deficiency on lipopolysaccharide (LPS)-induced liver injury and endotoxin shock in Propionibacterium acnes-primed mice. P. acnes-primed IL-18-deficient (IL-18KO) mice showed resistance to LPS-induced liver injury. Unexpectedly, P. acnes-primed IL-18KO mice were highly susceptible to LPS-induced endotoxin shock. Serum level of tumor necrosis factor (TNF)-alpha were markedly elevated (approximately 10-fold higher) within 1.5 h after LPS challenge in IL-18KO mice as compared with wild-type mice. Anti-TNF-alpha antibody administration to IL-18KO mice was significantly protective against endotoxin-induced lethality. P. acnes-primed IL-18KO macrophages produced approximately 6-fold more TNF-alpha protein than did P. acnes-primed wild-type control macrophages. Taken together, these findings demonstrate that IL-18 is responsible for the progression of endotoxin-induced liver injury as well as down-regulation of endotoxin-induced TNF-alpha production in P. acnes-primed mice.
Sakao
Y
Y
Department of Biochemistry, Hyogo College of Medicine, Nishinomiya, Japan.
Takeda
K
K
Tsutsui
H
H
Kaisho
T
T
Nomura
F
F
Okamura
H
H
Nakanishi
K
K
Akira
S
S
D000818:Animals; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D008099:Liver / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011425:Propionibacterium acnes / Q000276:immunology; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D020382:Interleukin-18; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12