Virchows Archiv

, Volume 446, Issue 6, pp 663–673

A murine model of NKT cell-mediated liver injury induced by alpha-galactosylceramide/d-galactosamine

  • Hideki Fujii
  • Shuichi Seki
  • Sawako Kobayashi
  • Takuya Kitada
  • Nobuyoshi Kawakita
  • Keishi Adachi
  • Hiroko Tsutsui
  • Kenji Nakanishi
  • Hiromi Fujiwara
  • Yoshinori Ikarashi
  • Masaru Taniguchi
  • Kronenberg Mitchell
  • Masaru Ikemoto
  • Yuji Nakajima
  • Tetsuo Arakawa
  • Kenji Kaneda
Original Article

DOI: 10.1007/s00428-005-1265-8

Cite this article as:
Fujii, H., Seki, S., Kobayashi, S. et al. Virchows Arch (2005) 446: 663. doi:10.1007/s00428-005-1265-8

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-α) and Fas in pathogenesis. We injected intraperitoneally alpha-galactosylceramide (α-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 Vα14NKT knock out (KO) mice did not develop liver injury. Tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) were elevated at 4 h in the plasma. These cytokines were produced by hepatic lymphocytes as demonstrated by in vitro stimulation with α-GalCer. The lethal effect was suppressed in TNF-α KO mice, TNF receptor-1 KO mice, and lpr/lpr (Fas deficient) mice, whereas it was not in IFN-γ KO mice. These results indicate that the present liver injury is characterized by parenchymal hemorrhage and hepatocyte apoptosis, and mediated by TNF-α secretion and direct cytotoxicity of α-GalCer-activated NKT cells.

Keywords

Parenchyma hemorrhageApoptosisTNF-αIFN-γFas

Abbreviations

NK

natural killer

NKT

natural killer-T

α-GalCer

alpha-galactosylceramide

GalN

d-galactosamine

SEB

staphylococcal enterotoxin B

TNF-α

tumor necrosis factor alpha

IFN-γ

interferon gamma

TNFR1

TNF receptor-1

FasL

Fas ligand

LPS

lipopolysaccharide

iNKT

invariant NKT

KO

knock out

mAb

monoclonal antibody

ALT

alanine transaminase

IL

interleukin

TUNEL

terminal deoxynucleotidyl transferase-mediated nick end labeling

WT

wild type

SECs

sinusoidal endothelial cells

RT-PCR

reverse transcription- polemerase chain reaction

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Hideki Fujii
    • 1
    • 2
  • Shuichi Seki
    • 1
  • Sawako Kobayashi
    • 1
  • Takuya Kitada
    • 1
  • Nobuyoshi Kawakita
    • 1
  • Keishi Adachi
    • 3
  • Hiroko Tsutsui
    • 3
    • 4
  • Kenji Nakanishi
    • 3
    • 4
  • Hiromi Fujiwara
    • 5
  • Yoshinori Ikarashi
    • 6
  • Masaru Taniguchi
    • 7
    • 8
  • Kronenberg Mitchell
    • 9
  • Masaru Ikemoto
    • 2
  • Yuji Nakajima
    • 2
  • Tetsuo Arakawa
    • 10
  • Kenji Kaneda
    • 2
  1. 1.Department of HepatologyOsaka City University Graduate School of MedicineOsakaJapan
  2. 2.Department of AnatomyOsaka City University Graduate School of MedicineOsakaJapan
  3. 3.Core Research for Evolutional Science and TechnologyJapan Science and Technology AgencyKawaguchiJapan
  4. 4.Department of Immunology and Medical ZoologyHyogo College of MedicineNishinomiyaJapan
  5. 5.Biomedical Research CenterOsaka University Graduate School of MedicineSuitaJapan
  6. 6.Pharmacology DivisionNational Cancer Center Research InstituteTokyoJapan
  7. 7.Institute of Physical and Chemical ResearchResearch Center for Allergy and ImmunologyTokyoJapan
  8. 8.Chiba University Graduate School of MedicineChibaJapan
  9. 9.La Jolla Institute for Allergy and ImmunologySan DiegoUSA
  10. 10.Department of GastoroenterologyOsaka City University Graduate School of MedicineOsakaJapan