A Murine Model of NKT Cell-mediated Liver Injury Induced by Alpha-galactosylceramide/d-galactosamine

Overview

Journal Virchows Arch

Specialties Cell Biology
Molecular Biology
Pathology

Date 2005 May 21

PMID 15906084

Citations 7

Authors

Hideki Fujii

Shuichi Seki

Sawako Kobayashi

Takuya Kitada

Nobuyoshi Kawakita

Keishi Adachi

Hiroko Tsutsui

Kenji Nakanishi

Hiromi Fujiwara

Yoshinori Ikarashi

Masaru Taniguchi

Mitchell Kronenberg

Kronenberg Mitchell

Masaru Ikemoto

Yuji Nakajima

Tetsuo Arakawa

Kenji Kaneda

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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Time-course analysis of liver and serum galectin-3 in acute liver injury after alpha-galactosylceramide injection.

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Glucosylceramide Administration as a Vaccination Strategy in Mouse Models of Cryptococcosis.

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