Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Gastroenterology. 2010 May;138(5):1885-97. doi: 10.1053/j.gastro.2010.01.051. Epub 2010 Feb 2.
BACKGROUND & AIMS: Pegylated interferon-alpha (PEG-IFNalpha), in combination with ribavirin, controls hepatitis C virus (HCV) infection in approximately 50% of patients by mechanisms that are not completely understood. Beside a direct antiviral effect, different immunomodulatory effects have been discussed. Natural killer (NK) cells might be associated with control of HCV infection. We examined the effects of IFNalpha on human NK cells and its relevance to HCV infection.
We performed gene expression profiling studies of NK cells following stimulation of peripheral blood mononuclear cells with IFNalpha. We evaluated IFNalpha-induced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression using flow cytometry analyses of NK cells isolated from patients with acute or chronic hepatitis C that had received PEG-IFNalpha therapy.
TRAIL was among the most up-regulated genes after IFNalpha stimulation of NK cells from healthy controls. After in vitro stimulation with IFNalpha, CD56(dim) NK cells from patients who had responded to PEG-IFNalpha therapy expressed higher levels of TRAIL than cells from patients with chronic hepatitis C. TRAIL expression, ex vivo, was inversely correlated with HCV-RNA levels during the early phase of PEG-IFNalpha therapy. In patients with acute hepatitis C, TRAIL expression on CD56(bright) NK cells increased significantly compared with cells from controls. In in vitro studies, IFNalpha-stimulated NK cells eliminated HCV-replicating hepatoma cells by a TRAIL-mediated mechanism.
IFNalpha-induced expression of TRAIL on NK cells is associated with control of HCV infection; these observations might account for the second-phase decline in HCV-RNA levels during PEG-IFNalpha therapy.
聚乙二醇干扰素-α（PEG-IFNα）联合利巴韦林通过部分尚未完全阐明的机制，可使约 50%的丙型肝炎病毒（HCV）感染患者得到控制。除了直接的抗病毒作用外，还讨论了不同的免疫调节作用。自然杀伤（NK）细胞可能与 HCV 感染的控制有关。我们研究了 IFNα 对人 NK 细胞的影响及其与 HCV 感染的相关性。
我们对经 IFNα刺激后的外周血单个核细胞中的 NK 细胞进行了基因表达谱研究。我们使用流式细胞术分析了来自接受 PEG-IFNα治疗的急性或慢性丙型肝炎患者的 NK 细胞，评估了 IFNα诱导的肿瘤坏死因子相关凋亡诱导配体（TRAIL）的表达。
TRAIL 是 NK 细胞经 IFNα刺激后上调最明显的基因之一。与慢性丙型肝炎患者相比，对 PEG-IFNα治疗有反应的患者的 NK 细胞中 CD56(dim)NK 细胞在体外经 IFNα刺激后表达更高水平的 TRAIL。TRAIL 表达与 PEG-IFNα治疗早期的 HCV-RNA 水平呈负相关。在急性丙型肝炎患者中，与对照组相比，CD56(bright)NK 细胞上的 TRAIL 表达显著增加。在体外研究中，IFNα 刺激的 NK 细胞通过 TRAIL 介导的机制消除 HCV 复制的肝癌细胞。
NK 细胞上 IFNα 诱导的 TRAIL 表达与 HCV 感染的控制有关；这些观察结果可能解释了 PEG-IFNα 治疗期间 HCV-RNA 水平的第二阶段下降。
