Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage.
Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage.
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DOI：
10.1084/jem.20082152
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发表时间：
2009-08-03
期刊：
影响因子：
--
通讯作者：
Trautwein C
中科院分区：
文献类型：
--
作者：
Beraza N;Malato Y;Sander LE;Al-Masaoudi M;Freimuth J;Riethmacher D;Gores GJ;Roskams T;Liedtke C;Trautwein C
核因子κB（NF-κB）是参与调节细胞凋亡、炎症、慢性肝病和癌症进展的主要转录因子之一。IKK复合物介导NF-κB活化，并在肝细胞中缺失其调节亚基NEMO（NEMOΔhepa），引发慢性炎症和自发性肝细胞癌的发生。我们发现NEMOΔhepa小鼠对Fas介导的细胞凋亡有抵抗力，但对肿瘤坏死因子相关凋亡诱导配体（TRAIL）高度敏感，这是由于其受体DR 5在肝细胞上的强烈上调。此外，自然杀伤（NK）细胞，TRAIL的主要来源，在NEMOΔhepa肝脏中被激活。有趣的是，NK1.1+细胞的耗竭促进了NEMOΔhepa小鼠肝脏炎症的显著减少和肝脏组织学的改善。此外，肝细胞特异性NEMO缺失强烈致敏肝刀豆球蛋白A（ConA）介导的损伤。NK细胞/TRAIL轴在ConA肝炎期间NEMOΔhepa肝脏中的关键作用通过选择性NK细胞耗竭和TRAIL缺陷型−/−单核细胞的过继转移得到进一步证实。我们的研究结果揭示了NEMO介导的肝脏保护的基本机制，通过TRAIL/DR 5信号传导防止NK细胞组织损伤。由于这种机制在人类肝脏疾病中很重要，NEMOΔhepa小鼠是一种有趣的工具，可以深入了解肝脏病理生理学并开发未来的治疗策略。
Nuclear factor κB (NF-κB) is one of the main transcription factors involved in regulating apoptosis, inflammation, chronic liver disease, and cancer progression. The IKK complex mediates NF-κB activation and deletion of its regulatory subunit NEMO in hepatocytes (NEMOΔhepa) triggers chronic inflammation and spontaneous hepatocellular carcinoma development. We show that NEMOΔhepa mice were resistant to Fas-mediated apoptosis but hypersensitive to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as the result of a strong up-regulation of its receptor DR5 on hepatocytes. Additionally, natural killer (NK) cells, the main source of TRAIL, were activated in NEMOΔhepa livers. Interestingly, depletion of the NK1.1+ cells promoted a significant reduction of liver inflammation and an improvement of liver histology in NEMOΔhepa mice. Furthermore, hepatocyte-specific NEMO deletion strongly sensitized the liver to concanavalin A (ConA)–mediated injury. The critical role of the NK cell/TRAIL axis in NEMOΔhepa livers during ConA hepatitis was further confirmed by selective NK cell depletion and adoptive transfer of TRAIL-deficient−/− mononuclear cells. Our results uncover an essential mechanism of NEMO-mediated protection of the liver by preventing NK cell tissue damage via TRAIL/DR5 signaling. As this mechanism is important in human liver diseases, NEMOΔhepa mice are an interesting tool to give insight into liver pathophysiology and to develop future therapeutic strategies.
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影响因子：
50.3
作者：
Luedde, Tom;Beraza, Naiara;Pasparakis, Manolis
通讯作者：
Pasparakis, Manolis
影响因子：
13.5
作者：
Guebre-Xabier, M;Yang, SQ;Diehl, AM
通讯作者：
Diehl, AM
影响因子：
13.5
作者：
Louis, H;LeMoine, O;Deviere, J
通讯作者：
Deviere, J
DOI：
10.1084/jem.193.6.661
发表时间：
2001-03-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Smyth MJ;Cretney E;Takeda K;Wiltrout RH;Sedger LM;Kayagaki N;Yagita H;Okumura K
通讯作者：
Okumura K
影响因子：
29.4
作者：
Beraza, Naiara;Ludde, Tom;Trautwein, Christian
通讯作者：
Trautwein, Christian