Kawabata Toshinobu, Kinoshita Manabu, Inatsu Akihito, Habu Yoshiko, Nakashima Hiroyuki, Shinomiya Nariyoshi, Seki Shuhji
Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan.
Hepatology. 2008 Nov;48(5):1586-97. doi: 10.1002/hep.22489.
Immune functions of liver natural killer T (NKT) cells induced by the synthetic ligand alpha-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.
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.
合成配体α-半乳糖神经酰胺诱导的肝脏自然杀伤T（NKT）细胞的免疫功能随年龄增长而增强；配体激活的NKT细胞诱导的肝损伤和多器官功能障碍综合征（MODS）也增强。本研究调查了衰老如何影响常见细菌DNA刺激后肝脏的固有免疫。将年轻（6周）和年老（50 - 60周）的C57BL/6小鼠注射CpG寡脱氧核苷酸（CpG-ODN），并评估肝脏白细胞的功能。向老年小鼠注射CpG-ODN显著增加了库普弗细胞中肿瘤坏死因子（TNF）的产生，并诱导了MODS和致死性休克，而这在年轻小鼠中很少见。老年库普弗细胞显示Toll样受体-9表达增加，并且CpG-ODN刺激增强了肝脏NKT细胞中TNF受体和Fas-L的表达。使用抗去唾液酸GM1抗体（Ab）使自然杀伤（NK）细胞耗竭的小鼠、穿孔素基因敲除小鼠以及用中和干扰素（IFN）-γ Ab预处理的小鼠进行的实验证明了肝脏NK细胞在抗肿瘤免疫中的重要作用。老年小鼠产生IFN-γ、IFN-α和穿孔素的能力远低于年轻小鼠，并且CpG诱导的肝脏NK细胞抗肿瘤细胞毒性减弱。在TNF、FasL或NKT细胞耗竭/缺陷的老年小鼠中，致死性休克和MODS显著降低。然而，NK细胞的耗竭也降低了血清TNF水平和NKT细胞的FasL表达，这导致肝损伤改善和存活率提高，表明NK细胞间接参与了NKT细胞诱导的MODS/致死性休克。TNF的中和并未降低CpG诱导的肝脏抗肿瘤作用。
CpG注射后，NKT细胞通过TNF和FasL介导的途径介导的肝损伤和MODS增加，但肝脏NK细胞的抗肿瘤活性随衰老而降低。
