NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner
NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner
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DOI：
10.1038/labinvest.2012.54
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发表时间：
2012-07-01
影响因子：
5
通讯作者：
Nattermann, Jacob
中科院分区：
文献类型：
--
作者：
Glaessner, Andreas;Eisenhardt, Marianne;Nattermann, Jacob
在小鼠模型中，已显示自然杀伤（NK）细胞可通过以NKG 2D和肿瘤坏死因子相关凋亡诱导配体（TRAIL）依赖性方式杀伤活化的肝星状细胞（HSC）来减轻肝纤维化。然而，关于人类NK细胞与HSC的相互作用及其在丙型肝炎病毒（HCV）相关纤维化中的潜在作用的数据很少。因此，将来自未经治疗的HCV RNA（+）患者（n = 33）、干扰素-α（IFN-α）治疗的患者（n = 17）和健康对照（n = 18）的纯化NK细胞与活化的原代HSC共孵育，并分别测试脱粒（CD 107 a表达）和IFN-γ和TNF-α的分泌。使用活性半胱天冬酶-3测定分析HSC凋亡的诱导。我们发现，在与HSC共孵育后，在来自HCV（+）患者和健康对照的NK细胞中可以观察到CD 107 a表达的显著增加，而仅可以检测到可忽略的IFN-γ和TNF-α分泌。更重要的是，未经治疗的HCV RNA（+）患者的NK细胞在诱导HSC凋亡方面（17.8 +/- 9.2%）比健康对照组的NK细胞（6.2 +/- 2.1%; P < 0.0001）更有效。此外，我们观察到肝纤维化阶段和NK细胞诱导HSC凋亡的能力呈负相关。HSC凋亡的诱导是接触依赖性的，并且可以分别被TRAIL、NKG 2D和FasL特异性抗体部分阻断。值得注意的是，来自IFN-α治疗的HCV（+）患者的NK细胞显示出杀死HSC的最高能力（27.6 +/-10.5%）。因此，用重组IFN-α预刺激NK细胞显著增加了NK细胞诱导原代HSC中细胞死亡的能力，并且依赖于TRAIL的上调表达。在这里，我们证明了来自HCV感染患者的NK细胞在诱导活化的HSC凋亡方面是高效的。因此，NK细胞可能在慢性丙型肝炎中具有重要的抗纤维化作用。实验室调查（2012）92，967-977; doi：10.1038/labinvest.2012.54; 2012年3月26日在线发表
In mouse models it has been shown that natural killer (NK) cells can attenuate liver fibrosis via killing of activated hepatic stellate cells (HSCs) in a NKG2D- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent manner. However, only little data exist regarding interactions of human NK cells with HSCs and their potential role in hepatitis C virus (HCV)-associated fibrogenesis. Therefore, purified NK cells from untreated HCV RNA(+) patients (n = 33), interferon-alpha (IFN-alpha)-treated patients (n = 17) and healthy controls (n = 18) were coincubated with activated primary HSCs, and were tested for degranulation (CD107a expression) and secretion of IFN-gamma and TNF-alpha, respectively. Induction of HSC apoptosis was analyzed using an active caspase-3 assay. We found that following coincubation with HSCs a significant increase in CD107a expression could be observed in both NK cells from HCV(+) patients and healthy controls, whereas only negligible secretion of IFN-gamma and TNF-alpha could be detected. More importantly, NK cells from untreated HCV RNA(+) patients were significantly more effective in induction of HSC apoptosis (17.8 +/- 9.2%) than NK cells from healthy controls (6.2 +/- 2.1%; P < 0.0001). Additionally, we observed an inverse correlation of liver fibrosis stage and the ability of NK cells to induce HSC apoptosis. Induction of HSC apoptosis was contact dependent and could partly be blocked by antibodies specific for TRAIL, NKG2D and FasL, respectively. It is noteworthy that NK cells from IFN-alpha-treated HCV(+) patients displayed the highest capability to kill HSCs (27.6 +/- 10.5%). Accordingly, pre-stimulation of NK cells with recombinant IFN-alpha significantly increased the ability of NK cells to induce cell death in primary HSCs and was dependent on upregulated expression of TRAIL. Here we demonstrate that NK cells from HCV-infected patients are highly efficient in inducing apoptosis of activated HSCs. Thus, NK cells may have an important anti-fibrotic role in chronic hepatitis C. Laboratory Investigation (2012) 92, 967-977; doi:10.1038/labinvest.2012.54; published online 26 March 2012