Li Bofeng, Sun Rui, Wei Haiming, Gao Bin, Tian Zhigang
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
Hepatology. 2006 Jun;43(6):1211-9. doi: 10.1002/hep.21174.
Administration of concanavalin A (Con A) induces a rapid and severe liver injury in mice. Natural killer T (NKT) cells are recognized to be the key effector cells, and a variety of cytokines [e.g., interleukin 4 (IL-4), IL-5, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha)] have been shown to play vital roles in Con A-induced liver injury, whereas the role of IL-15, a critical cytokine in the development and homeostasis of NKT cells, remains obscure. In this study, pretreatment with IL-15 prevented mice from Con A-induced mortality, elevation of serum transaminase, liver necrosis, and hepatocyte apoptosis. Depletion of NKT cells abolished Con A-induced liver injury, which could be restored by adoptive transfer of purified NKT cells but not by that of in vivo or in vitro IL-15-treated hepatic NKT cells. Furthermore, transfer of wild-type NKT cells to CD1d-/- mice restored liver injury, whereas transfer of IL-15-treated NKT cells did not. IL-15 pretreatment decreased the NKT-derived IL-4, IL-5, and TNF-alpha production, thereby resulting in less infiltration of eosinophils, which play a critical role in Con A-induced liver injury. In conclusion, IL-15 protects against Con A-induced liver injury via an NKT cell-dependent mechanism by reducing their production of IL-4, IL-5, and infiltration of eosinophils. These findings suggest that IL-15 may be of therapeutic relevance in human autoimmune-related hepatitis.
注射伴刀豆球蛋白A（Con A）可在小鼠中诱导快速且严重的肝损伤。自然杀伤T（NKT）细胞被认为是关键效应细胞，多种细胞因子[如白细胞介素4（IL-4）、IL-5、干扰素γ（IFN-γ）和肿瘤坏死因子α（TNF-α）]已被证明在Con A诱导的肝损伤中起重要作用，而IL-15作为NKT细胞发育和稳态中的关键细胞因子，其作用仍不清楚。在本研究中，用IL-15预处理可防止小鼠因Con A诱导的死亡、血清转氨酶升高、肝坏死和肝细胞凋亡。NKT细胞的耗竭消除了Con A诱导的肝损伤，通过纯化NKT细胞的过继转移可恢复该损伤，但体内或体外经IL-15处理的肝NKT细胞的过继转移则不能恢复。此外，将野生型NKT细胞转移到CD1d-/-小鼠可恢复肝损伤，而转移经IL-15处理的NKT细胞则不能。IL-15预处理降低了NKT细胞衍生的IL-4、IL-5和TNF-α的产生，从而导致嗜酸性粒细胞浸润减少，而嗜酸性粒细胞在Con A诱导的肝损伤中起关键作用。总之，IL-15通过减少NKT细胞产生IL-4、IL-5以及嗜酸性粒细胞浸润，经由NKT细胞依赖性机制预防Con A诱导的肝损伤。这些发现表明IL-15可能与人类自身免疫性肝炎的治疗相关。
