title: IL-18 accounts for both TNF-alpha- and Fas ligand-mediated hepatotoxic pathways in endotoxin-induced liver injury in mice.
abstract: When LPS is administered to heat-killed Propionibacterium acnes-primed BALB/c nude mice, they develop endotoxin-induced liver injury. As previously reported, this liver injury can be prevented by treatment with an Ab against IL-18, a novel cytokine with the ability to induce IFN-gamma production and up-regulate functional Fas ligand (FasL) expression. To identify the pathologic role of IL-18 in this liver injury, we investigated the hepatic cytokine network and FasL induction after LPS challenge. After LPS challenge to BALB/c nude mice, their livers expressed IL-12 mRNA, followed by the induction of IFN-gamma and FasL mRNA and then by the late elevation of TNF-alpha mRNA, but stably expressed IL-18 mRNA. The TNF-alpha induction curve had two peaks. The first peak was the result of the direct reaction to LPS, and the late peak might have been induced, since P. acnes-elicited Kupffer cells showed one-peak TNF-alpha kinetics in response to LPS stimulation in vitro. LPS-activated P. acnes-elicited Kupffer cells secreted both IL-12 and IL-18, as determined by ELISA and bioassay, respectively. The in vivo administration of anti-IL-18 just before an LPS challenge suppressed not only the induction of IFN-gamma and the late TNF-alpha elevation, but also the FasL induction, resulting in the total prevention of liver injury, whereas such an anti-IL-12 treatment did not. Anti-IFN-gamma treatment reduced the late increase in TNF-alpha, but not FasL, resulting in a partial prevention of the liver injury. The administration of anti-TNF-alpha just before elevation of the late TNF-alpha peak also markedly, but incompletely, suppressed the LPS-induced liver injury. These data suggested that IL-18 activates both TNF-alpha- and FasL-mediated hepatocytotoxic pathways in endotoxin-induced liver injury.
authors.affiliation: Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tsutsui
authors.forename: K
authors.initials: K
authors.lastname: Matsui
authors.forename: N
authors.initials: N
authors.lastname: Kawada
authors.forename: Y
authors.initials: Y
authors.lastname: Hyodo
authors.forename: N
authors.initials: N
authors.lastname: Hayashi
authors.forename: H
authors.initials: H
authors.lastname: Okamura
authors.forename: K
authors.initials: K
authors.lastname: Higashino
authors.forename: K
authors.initials: K
authors.lastname: Nakanishi
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000502:physiology*; D053222:Fas Ligand Protein; D007106:Immune Sera / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000276:immunology; D020382:Interleukin-18; D008024:Ligands; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011425:Propionibacterium acnes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007106:Immune Sera; D020382:Interleukin-18; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D018664:Interleukin-12