Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC
Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC
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DOI：
10.1016/j.jhep.2005.12.025
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发表时间：
2006-07-01
影响因子：
25.7
通讯作者：
Safadi, Rifaat
中科院分区：
文献类型：
--
作者：
Melhem, Alaa;Muhanna, Nidal;Safadi, Rifaat
背景/目的：我们研究了自然杀伤细胞（NK）在肝纤维化中的作用。小鼠NK细胞表达i类分子特异性的抑制/激活-杀伤免疫球蛋白相关受体（ikiir /aKIR）。方法：比较四氯化碳（CCl4）诱导的野生型（WT）雄性balbc的肝纤维化；联合免疫缺陷（SCID，缺乏B/ t细胞）；scid - beige小鼠（缺乏B/T/NK细胞）和幼稚小鼠。结果：ccl4治疗组肝纤维化明显加重。通过天狼星红染色组织切片的形态测定，SCID-BEIGE小鼠的纤维化程度高于scid小鼠（P < 0.0001）。纤维化后，肝NK细胞显著减少，aKIR: ikir -比值显著升高，HSC中Class-I表达降低（P < 0.001）。新鲜分离的和原位的HSC在纤维化诱导后显示出细胞凋亡的显著增加。共聚焦显微镜显示NK细胞与小鼠肝切片和体外人NK/HSC共培养的HSC直接粘附。在人HSC中，i类表达减少，细胞凋亡增加，在阻断HSC相关的i类或nk相关的杀伤抑制受体后，细胞凋亡进一步增加。用颗粒酶抑制剂3,4-二氯异香豆素预孵育NK细胞可抑制细胞凋亡。结论：在肝损伤期间，NK细胞至少部分通过刺激HSC杀伤而具有抗纤维化活性。(c) 2006欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background/Aims: We have investigated the role of natural killer (NK) cells in hepatic fibrogenesis. Mouse NK cells express both inhibitory/activating-killing-immunoglobulin-related-receptors (iKIR/aKIR) specific for Class-I-molecules.Methods: Hepatic fibrosis induced by carbon-tetrachloride (CCl4) was compared between wild-type (WT) male-BALBc; combined-immunodeficiency (SCID, lacking B/T-cells); and SCID-BEIGE-mice (lacking B/T/NK cells), and naive mice.Results: Hepatic fibrosis significantly increased in all CCl4-treated groups. SCID-BEIGE mice had more fibrosis than SCID-mice (P < 0.0001) as assessed by morphometry of sirius-red stained tissue sections. Following fibrosis, hepatic NK cells significantly decreased, the aKIR:iKIR-ratio significantly increased while Class-I expression on HSC decreased (P < 0.001). Both freshly isolated and in situ HSC displayed a significant increase in cellular apoptosis following fibrosis induction. Confocal microscopy demonstrated the direct adhesion of NK cells to HSC in mouse liver sections and in vitro human NK/HSC co-culture. In human HSC there was decreased Class-I expression and increased apoptosis as well, which was further increased following blocking of either HSC-related Class-I or NK-related killer inhibitory receptors. Apoptosis was inhibited by pre-incubation of NK cells with the granzyme inhibitor 3,4-dichloroisocoumarin.Conclusions: During liver injury, NK cells have an anti-fibrotic activity at least in part through stimulation of HSC killing. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.