Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners
Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners
复制标题
DOI：
10.1053/j.gastro.2005.10.055
复制
发表时间：
2006-02-01
期刊：
影响因子：
29.4
通讯作者：
Gao, B
中科院分区：
文献类型：
--
作者：
Radaeva, S;Sun, R;Gao, B
背景与目的：病毒性肝炎是肝纤维化的主要原因，与先天免疫的激活有关。然而，先天免疫在肝纤维化中的作用仍然不清楚。研究方法：通过给小鼠喂食3，5-二乙氧羰基-1，4-二氢可力丁（DDC）饲料或注射四氯化碳诱导肝纤维化。Toll样受体3配体，聚肌胞，被用来激活先天免疫细胞和介质，包括自然杀伤细胞和干扰素T。结果如下：在DDC诱导的肝纤维化小鼠模型中，聚肌胞-聚肌胞酸激活的自然杀伤细胞诱导活化的肝星状细胞的细胞死亡，并减轻肝纤维化的严重程度。聚肌胞治疗也改善四氯化碳诱导的肝纤维化。所观察到的聚肌胞对肝纤维化的保护作用通过自然杀伤细胞的耗竭或干扰素T基因的破坏而减弱。维甲酸早期诱导1，NKG 213配体的表达，是不可检测的静止肝星状细胞，而高水平上发现活化的肝星状细胞，这与静止肝星状细胞和活化的肝星状细胞自然杀伤细胞裂解的阻力和敏感性，分别。此外，用聚肌胞苷酸或干扰素γ治疗增强了自然杀伤细胞对活化的肝星状细胞的细胞毒性，并增加了肝自然杀伤细胞上NKG 2D和肿瘤坏死因子相关凋亡诱导配体的表达。用中和抗体阻断NKG 2D或肿瘤坏死因子相关凋亡诱导配体可显著降低聚肌胞激活的自然杀伤细胞对激活的肝星状细胞的细胞毒性。结论：我们的研究结果表明，自然杀伤细胞通过视黄酸早期诱导1/NKG 2D依赖性和肿瘤坏死因子相关的凋亡诱导配体依赖性机制杀死活化的肝星状细胞，从而改善肝纤维化。
Background & Aims: Viral hepatitis infection, which is a major cause of liver fibrosis, is associated with activation of innate immunity. However, the role of innate immunity in liver fibrosis remains obscure. Methods: Liver fibrosis was induced either by feeding mice with the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet or by injecting them with carbon tetrachloride. The Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid, was used to activate innate immunity cells and mediators, including natural killer cells and interferon T. Results: In the mouse model of DDC-induced liver fibrosis, natural killer cell activation by polyinosinic-polycytidylic acid induced cell death to activated hepatic stellate cells and attenuated the severity of liver fibrosis. Polyinosinic-polycytidylic acid treatment also ameliorated liver fibrosis induced by carbon tetrachloride. The observed protective effect of polyinosinic-polycytidylic acid on liver fibrosis was diminished through either depletion of natural killer cells or by disruption of the interferon T gene. Expression of retinoic acid early inducible 1, the NKG213 ligand, was undetectable on quiescent hepatic stellate cells, whereas high levels were found on activated hepatic stellate cells, which correlated with the resistance and susceptibility of quiescent hepatic stellate cells and activated hepatic stellate cells to natural killer cell lysis, respectively. Moreover, treatment with polyinosinic-polycytidylic acid or interferon gamma enhanced the cytotoxicity of natural killer cells against activated hepatic stellate cells and increased the expression of NKG2D and tumor necrosis factor-related apoptosis-inducing ligand on liver natural killer cells. Blocking NKG2D or tumor necrosis factor-related apoptosis-inducing ligand with neutralizing antibodies markedly diminished the cytotoxicity of polyinosinic-polycytidylic acid-activated natural killer cells against activated hepatic stellate cells. Conclusions: Our findings suggest that natural killer cells kill activated hepatic stellate cells via retinoic acid early inducible 1/NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent mechanisms, thereby ameliorating liver fibrosis.