Activation of mouse natural killer T cells accelerates liver regeneration after partial hepatectomy.
OBJECTIVE
Activation of natural killer T cells with the synthetic ligand alpha-galactosylceramide (alpha-GalCer) induced hepatotoxicity through the tumor necrosis factor (TNF) and Fas-ligand-mediated pathway in aged mice. The aim of this study was to elucidate how alpha-GalCer-activated natural killer T cells function in hepatocyte proliferation and liver regeneration in partially hepatectomized (PHx) mice.


METHODS
Mice were injected with alpha-GalCer at 36 hours after 70% PHx. Hepatocyte mitosis was evaluated by either mitotic figures or proliferating cell nuclear antigen staining. The role of TNF and Fas-ligand in hepatocyte mitosis also was assessed.


RESULTS
In PHx mice injected with alpha-GalCer, hepatocyte mitosis was greatly enhanced at 44 hours after surgery and the increase was more obvious in aged mice than in young mice. The expression of both TNF receptor 1 and Fas-ligand in liver natural killer T cells tended to increase after alpha-GalCer injection in PHx mice. Treatment of mice with anti-NK1.1 Ab 3 days before and just after hepatectomy greatly inhibited the effect of alpha-GalCer on hepatocyte mitosis and liver regeneration. Furthermore, pretreatment of PHx mice with either anti-TNF Ab or anti-FasL Ab 1 hour before alpha-GalCer injection mostly abrogated the increase in hepatocyte proliferation. alpha-GalCer injection did not accelerate hepatocyte proliferation in Fas-mutated lpr mice after PHx. CD1d-/- mice without alpha-GalCer injection showed decreased hepatocyte mitosis after PHx.


CONCLUSIONS
Activated natural killer T cells help hepatocyte proliferation and liver regeneration after PHx via the TNF and Fas/Fas-ligand-mediated pathway.
Nakashima
Hiroyuki
H
Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan.
Inui
Takuo
T
Habu
Yoshiko
Y
Kinoshita
Manabu
M
Nagao
Shigeaki
S
Kawaguchi
Atsushi
A
Miura
Soichiro
S
Shinomiya
Nariyoshi
N
Yagita
Hideo
H
Seki
Shuhji
S
D000818:Animals; D053222:Fas Ligand Protein / Q000032:analysis / Q000502:physiology; D005699:Galactosylceramides / Q000494:pharmacology; D006498:Hepatectomy; D007694:Killer Cells, Natural / Q000276:immunology*; D008115:Liver Regeneration; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008938:Mitosis; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000032:analysis / Q000502:physiology
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D005699:Galactosylceramides; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; C493154:alpha-galactosylceramide