Neutralization of tumor necrosis factor abrogates hepatic failure induced by α-galactosylceramide without attenuating its antitumor effect in aged mice
Neutralization of tumor necrosis factor abrogates hepatic failure induced by α-galactosylceramide without attenuating its antitumor effect in aged mice
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DOI：
10.1016/j.jhep.2005.02.027
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发表时间：
2005-10-01
影响因子：
25.7
通讯作者：
Seki, S
中科院分区：
文献类型：
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作者：
Inui, T;Nakashima, H;Seki, S
背景/目标：用α-半乳糖神经酰胺（α-GalCer）刺激的小鼠肝脏NK1.1（+）T（NKT）细胞的功能增强具有年龄依赖性，并且肝脏中的抗肿瘤和抗转移作用依赖于IFN-γ。然而，肝损伤不依赖于IFN-γ和Fas/Fas-配体依赖性。本研究的目的是探讨肿瘤坏死因子是如何参与α-GalCer介导的免疫现象。方法：C57 BL/6小鼠在注射α-GalCer前1 h腹腔注射抗TNF抗体，观察NKT细胞Fas配体表达，血清ALT水平，肝、肾、肺组织病理学改变，以及注射α-GalCer后的死亡率。IFN-γ的生产和抗肿瘤免疫力的EL-4细胞静脉注射后的肝脏也assessed.Results：α-GalCer注射后血清TNF水平增加小鼠的年龄依赖性。抗TNF抗体降低NKT细胞的Fas-配体（Fas-L）表达，同时完全抑制α-GalCer诱导的器官损伤，从而降低老年小鼠的死亡率，而它不影响NKT细胞产生IFN-γ，肝脏中的抗肿瘤免疫，也不影响EL-4注射后小鼠的存活率。α-半乳糖神经酰胺激活的NKT细胞分别参与IFN-γ和TNF/Fas-L的抗肿瘤免疫或肝损伤。(c)2005年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: The functions of mouse liver NK1.1(+) T (NKT) cells stimulated with alpha-galactosylceramide (alpha-GalCer) are enhanced age dependently, and the antitumor and anti-metastatic effect in the liver is dependent on IFN-gamma. However, hepatic injury is independent of IFN-gamma and Fas/Fas-ligand dependent. The aim of this study is to investigate how tumor necrosis factor is involved in the alpha-GalCer-mediated immune phenomena.Methods: C57BL/6 mice were intraperitoneally treated with anti-TNF antibody 1 h before alpha-GalCer injection, and Fas-ligand expression of NKT cells, the serum ALT levels and histopathological findings of the liver, kidney and lung and mortality after alpha-GalCer injection were evaluated. IFN-gamma production and antitumor immunity in the liver after the intravenous injection of EL-4 cells were also assessed.Results: Serum TNF levels after alpha-GalCer injection increased age dependently in mice. Anti-TNF Ab reduced Fas-ligand (Fas-L) expression of NKT cells while it completely inhibited organ injuries induced by alpha-GalCer and thereby reduced the mortality of old mice, whereas it did not affect the IFN-gamma production from NKT cells, the antitumor immunity in the liver nor the mouse survival after EL-4 injection.Conclusions: NKT cells activated by alpha-galactosylceramide participated in either antitumor immunity or hepatic injury using IFN-gamma and TNF/Fas-L, respectively. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.