Activation of mouse natural killer T cells accelerates liver regeneration after partial hepatectomy |
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Authors: | Nakashima Hiroyuki Inui Takuo Habu Yoshiko Kinoshita Manabu Nagao Shigeaki Kawaguchi Atsushi Miura Soichiro Shinomiya Nariyoshi Yagita Hideo Seki Shuhji |
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Institution: | Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan. |
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Abstract: | BACKGROUND & AIMS: 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. |
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Keywords: | Ab antibody α-GalCer α-galactosylceramide FasL Fas-ligand IFN interferon MNC mononuclear cell NKT natural killer T PCNA proliferating cell nuclear antigen PCR polymerase chain reaction PHx partial hepatectomy or partially hepatectomized SE standard error TCR T-cell receptor TNF tumor necrosis factor TNFR1 tumor necrosis factor receptor 1 |
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