Functional Alterations of Liver Innate Immunity of Mice with Aging in Response to CpG-Oligodeoxynucleotide
Functional Alterations of Liver Innate Immunity of Mice with Aging in Response to CpG-Oligodeoxynucleotide
复制标题
DOI：
10.1002/hep.22489
复制
发表时间：
2008-11-01
期刊：
影响因子：
13.5
通讯作者：
Seki, Shuhji
中科院分区：
文献类型：
--
作者：
Kawabata, Toshinobu;Kinoshita, Manabu;Seki, Shuhji
合成配体a-半乳糖神经酰胺诱导的肝脏自然杀伤T （NKT）细胞免疫功能的年龄依赖性增强配体活化的NKT细胞诱导的肝损伤和多器官功能障碍综合征（MODS）也增强。本研究探讨了衰老对普通细菌DNA刺激后肝脏先天免疫的影响。给幼龄（6周龄）和老年（50 ~ 60周龄）C57BL/6小鼠注射CpG寡脱氧核苷酸（CpG- odn），观察其肝脏白细胞功能。老年小鼠注射CpG-ODN显著增加Kupffer细胞中肿瘤坏死因子（TNF）的产生，并诱导MODS和致死性休克，这两种现象在年轻小鼠中罕见。老Kupffer细胞显示toll样受体-9表达增加，CpG-ODN挑战增强了肝NKT细胞中TNF受体和Fas-L的表达。通过抗asialogm1抗体（Ab）去除自然杀伤（NK）细胞的小鼠、穿孔素敲除小鼠和中和干扰素(IFN)- γ Ab预处理的小鼠的实验，证明了肝脏NK细胞在抗肿瘤免疫中的重要作用。老龄小鼠产生ifn - γ、ifn - α和穿孔素的能力明显低于年轻小鼠，cpg诱导的肝NK细胞抗肿瘤细胞毒性减弱。在TNF、FasL或NKT细胞缺失/缺乏的老年小鼠中，致死性休克和MODS显著降低。然而，NK细胞的消耗也降低了血清TNF水平和NKT细胞FasL的表达，从而改善了肝损伤和存活，提示NK细胞间接参与了NKT细胞诱导的MODS/致死性休克。TNF的中和不降低cpg诱导的肝脏抗肿瘤作用。结论：CpG注射后，NKT细胞经TNF和fasl介导途径介导的肝损伤和MODS增加，但肝脏NK细胞抗肿瘤活性随年龄增长而降低。(肝脏病学48:1586 2008;1597)。
Immune functions of liver natural killer T (NKT) cells induced by the synthetic ligand a-galactosylceramide enhanced age-dependently; hepatic injury and multiorgan dysfunction syndrome (MODS) induced by ligand-activated NKT cells were also enhanced. This study investigated how aging affects liver innate immunity after common bacteria DNA stimulation. Young (6 weeks) and old (50-60 weeks) C57BL/6 mice were injected with CpG oligodeoxynucleotides (CpG-ODN), and the functions of liver leukocytes were assessed. A CpG-ODN injection into the old mice remarkably increased tumor necrosis factor (TNF) production in Kupffer cells, and MODS and lethal shock were induced, both of which are rarely seen in young mice. Old Kupffer cells showed increased Toll-like receptor-9 expression, and CpG-ODN challenge augmented TNF receptor and Fas-L expression in liver NKT cells. Experiments using mice depleted of natural killer (NK) cells by anti-asialoGM1 antibody (Ab), perforin knockout mice, and mice pretreated with neutralizing interferon (IFN)-gamma Ab demonstrated the important role of liver NK cells in antitumor immunity. The production capacities of old mice for IFN-gamma, IFN-alpha, and perforin were much lower than those of young mice, and the CpG-induced antitumor cytotoxicity of liver NK cells lessened. Lethal shock and MODS greatly decreased in old mice depleted/deficient in TNF, FasL, or NKT cells. However, depletion of NK cells also decreased serum TNF levels and FasL expression of NKT cells, which resulted in improved hepatic injury and survival, suggesting that NK cells are indirectly involved in MODS/lethal shock induced by NKT cells. Neutralization of TNF did not reduce the CpG-induced antitumor effect in the liver. Conclusion: Hepatic injury and MODS mediated by NKT cells via the TNF and FasL-mediated pathway after CpG injection increased, but the antitumor activity of liver NK cells decreased with aging. (HEPATOLOGY 2008;48:1586-1597.)