NK cells suppress experimental cholestatic liver injury by an interleukin-6-mediated, Kupffer cell-dependent mechanism.
NK cells suppress experimental cholestatic liver injury by an interleukin-6-mediated, Kupffer cell-dependent mechanism.
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DOI：
10.1016/j.jhep.2010.07.018
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发表时间：
2011-04
影响因子：
25.7
通讯作者：
Gregory SH
中科院分区：
文献类型：
--
作者：
Cheng CW;Duwaerts CC;Rooijen Nv;Wintermeyer P;Mott S;Gregory SH
自然杀伤(NK)细胞是一种先天免疫效应细胞，其最初的特征是能够溶解敏感的肿瘤细胞。最近的研究表明，它们在启动和调节获得性免疫中发挥作用。NK细胞在肝脏淋巴组织中所占比例高于其他器官，提示肝脏NK细胞具有独特的功能。在这里，我们研究了NK细胞对发生在胆道梗阻小鼠模型中的肝损伤的反应。胆管结扎(BDL)是在先前耗尽或未耗尽NK细胞的小鼠上进行的。检测NK细胞活化、Kupffer细胞IL-6mRNA表达和蛋白生成，以及外源性IL-6对NK细胞耗竭小鼠肝损伤的改善作用。BDL后活化的肝NK细胞数量明显增加。在Kupffer细胞在结扎前耗尽的小鼠中，激活被抑制。NK细胞耗尽的小鼠肝损伤加重，与IL-6产生减少有关。从NK细胞耗尽或抗干扰素-γ单抗处理的小鼠获得的纯化的Kupffer细胞在培养中产生的IL-6比来自对照动物的Kupffer细胞少。在培养中，来自BDL小鼠的肝脏NK细胞刺激库普弗细胞产生依赖于干扰素γ的IL-6；来自相同动物的脾NK细胞的作用可以忽略不计。重组小鼠IL-6治疗可减轻BDL、NK细胞耗竭小鼠的肝损伤。肝NK细胞通过刺激Kupffer细胞依赖的IL-6产生抑制胆汁淤积性肝损伤。
Natural killer (NK) cells are innate immune effector cells first characterized by their ability to lyse susceptible tumor cells. Recent studies demonstrated their role in initiating and modulating adaptive immunity. NK cells represent a larger percentage of the lymphoid population in liver than other organs suggesting that hepatic NK cells express some unique function. Here, we examined the response of NK cells to liver injury that occurs in a mouse model of biliary obstruction. Bile duct ligations (BDL) were performed on mice previously depleted or not depleted of NK cells. NK cell activation, interleukin (IL)-6 mRNA expression and protein production by Kupffer cells, and the ability of exogenous IL-6 to ameliorate liver injury in NK cell-depleted mice were determined. The number of activated hepatic NK cells increased markedly following BDL. Activation was suppressed in mice rendered Kupffer cell-depleted prior to ligation. Increased liver injury occurred in NK cell-depleted mice correlating with a reduction in IL-6 production. Purified Kupffer cells obtained from NK cell-depleted or anti-interferon (IFN)-γ monoclonal antibody-pretreated mice following BDL produced less IL-6 in culture than did Kupffer cells derived from control animals. In culture, hepatic NK cells derived from BDL mice stimulated IFN-γ-dependent IL-6 production by Kupffer cells; splenic NK cells obtained from the same animals had a negligible effect. Treatment with recombinant murine IL-6 reduced liver injury in BDL, NK cell-depleted mice. Hepatic NK cells suppress cholestatic liver injury by stimulating Kupffer cell-dependent IL-6 production.
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