Activation of mouse natural killer T cells accelerates liver regeneration after partial hepatectomy

Background & Aims: Activation of natural killer T cells with the synthetic ligand alpha-galactosylceramide (a-GalCer) induced hepatoroxicity through the tumor necrosis factor (TNF) and Fas-ligand-mediated pathway in aged mice. The aim of this study was to elucidate how a-GalCer-activated natural killer T cells function in hepatocyte proliferation and liver regeneration in partially hepatectomized (PHx) mice. Methods: Mice were injected with a-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 a-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 a-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 a-GalCer on hepatocyte mitosis and liver regeneration. Furthermore pretreatment of PHx mice with either anti-TNF Ab or anti-FasL Ab I hour before a-GalCer injection mostly abrogated the increase in hepatocyte proliferation. a-GalCer injection did not accelerate hepatocyte proliferation in Fas-mutated lpr mice after PHx. CD1d-/- mice without a-GalCer injection showed decreased hepatocyte mitosis after PHx. Conclusions: Activated natural killer T cells help hepatocyte proliferation and liver regeneration after PHx via the TNT and Fas/Fas-ligand-mediated pathway.