A murine model of NKT cell-mediated liver injury induced by alpha-galactosylceramide/d-galactosamine.
Natural killer-T (NKT) cells are rich in the liver. However, their involvement in liver injury is not fully understood. We developed here a new murine model of NKT-cell-activation-associated liver injury, and investigated a role of tumor necrosis factor alpha (TNF-alpha) and Fas in pathogenesis. We injected intraperitoneally alpha-galactosylceramide (alpha-GalCer), an NKT-cell stimulant, into D-galactosamine (GalN)-sensitized mice. Survival rate, pathological changes of the liver, and plasma concentrations of cytokines were studied. Alpha-GalCer/GalN administration gave a lethal effect within 7 h, making pathological changes such as massive parenchymal hemorrhage, hepatocyte apoptosis, sinusoidal endothelial cell injury, and close apposition of lymphocytes to apoptotic hepatocytes. Anti-NK1.1 mAb-pretreated mice and Valpha14NKT knock out (KO) mice did not develop liver injury. Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were elevated at 4 h in the plasma. These cytokines were produced by hepatic lymphocytes as demonstrated by in vitro stimulation with alpha-GalCer. The lethal effect was suppressed in TNF-alpha KO mice, TNF receptor-1 KO mice, and lpr/lpr (Fas deficient) mice, whereas it was not in IFN-gamma KO mice. These results indicate that the present liver injury is characterized by parenchymal hemorrhage and hepatocyte apoptosis, and mediated by TNF-alpha secretion and direct cytotoxicity of alpha-GalCer-activated NKT cells.
Fujii
Hideki
H
Department of Hepatology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. rolahidek@med.osaka-cu.ac.jp
Seki
Shuichi
S
Kobayashi
Sawako
S
Kitada
Takuya
T
Kawakita
Nobuyoshi
N
Adachi
Keishi
K
Tsutsui
Hiroko
H
Nakanishi
Kenji
K
Fujiwara
Hiromi
H
Ikarashi
Yoshinori
Y
Taniguchi
Masaru
M
Kronenberg
Mitchell
M
Mitchell
Kronenberg
K
Ikemoto
Masaru
M
Nakajima
Yuji
Y
Arakawa
Tetsuo
T
Kaneda
Kenji
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005688:Galactosamine / Q000494:pharmacology; D005699:Galactosylceramides / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000097:blood / Q000172:deficiency / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology* / Q000293:injuries* / Q000473:pathology; D008107:Liver Diseases / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D005699:Galactosylceramides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide; D005688:Galactosamine; D007371:Interferon-gamma