单核细胞通过炎症小体诱导的白细胞介素 18 激活自然杀伤细胞，以响应丙型肝炎病毒复制。
Monocytes activate natural killer cells via inflammasome-induced interleukin 18 in response to hepatitis C virus replication.
机构信息
Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland.
出版信息
Gastroenterology. 2014 Jul;147(1):209-220.e3. doi: 10.1053/j.gastro.2014.03.046. Epub 2014 Mar 28.
BACKGROUND & AIMS: Production of interferon (IFN)-γ by natural killer (NK) cells is attenuated during chronic infection with hepatitis C virus (HCV). We investigated whether this is due to intrinsic or extrinsic mechanisms of NK cells.
METHODS
Peripheral blood mononuclear cells (PBMCs) were collected from patients with chronic HCV infection or uninfected blood donors (controls); NK cells and monocytes were isolated or eliminated. We cultured hepatoma cells that express luciferase-tagged subgenomic HCV replicons (Huh7/HCV replicon cells) or their HCV-negative counterparts (Huh7) with NK cells in the presence or absence of other populations of PBMCs. Antiviral activity, cytotoxicity, and cytokine production were assessed.
RESULTS
NK cells produced greater amounts of IFN-γ when PBMC were cocultured with Huh7/HCV replicon cells than with Huh7 cells; NK cells and PBMCs from controls suppressed HCV replication to a greater extent than those from patients with chronic HCV infection. This antiviral effect was predominantly mediated by tumor necrosis factor (TNF)-α and IFN-γ. The antiviral activity of NK cells and their production of IFN-γ were reduced when they were used in coculture alone (rather than with PBMC), or after depletion of CD14(+) monocytes, after knockdown of the inflammasome in monocytes, or after neutralization of interleukin-18, which is regulated by the inflammasome. These findings indicate a role for monocytes in NK cell activation. Compared with control monocytes, monocytes from patients with chronic HCV infection had reduced TNF-α-mediated (direct) and reduced NK cell-mediated (indirect) antiviral effects. Control monocytes increased the antiviral effects of NK cells from patients with chronic HCV infection and their production of IFN-γ.
CONCLUSIONS
Monocytes sense cells that contain replicating HCV and respond by producing interleukin-18 via the inflammasome and by activating NK cells. Patients with chronic HCV infection have reduced monocyte function, attenuating NK cell IFN-γ-mediated responses.
背景与目的
自然杀伤 (NK) 细胞产生干扰素 (IFN)-γ的能力在慢性丙型肝炎病毒 (HCV) 感染期间减弱。我们研究了这是否是由于 NK 细胞的内在或外在机制。
方法
从慢性 HCV 感染患者或未感染血液供体（对照）中采集外周血单核细胞（PBMC）；分离或消除 NK 细胞和单核细胞。我们培养表达荧光素酶标记亚基因组 HCV 复制子的肝癌细胞（Huh7/HCV 复制子细胞）或其 HCV 阴性对应物（Huh7），并在存在或不存在其他 PBMC 群体的情况下与 NK 细胞共培养。评估抗病毒活性、细胞毒性和细胞因子产生。
结果
当 PBMC 与 Huh7/HCV 复制子细胞共培养时，NK 细胞产生的 IFN-γ 量大于与 Huh7 细胞共培养时；对照者的 NK 细胞和 PBMC 比慢性 HCV 感染患者更能抑制 HCV 复制。这种抗病毒作用主要由肿瘤坏死因子 (TNF)-α 和 IFN-γ介导。当 NK 细胞单独用于共培养（而不是与 PBMC 一起）时，或在耗尽 CD14(+)单核细胞、敲低单核细胞中的炎症小体或中和白细胞介素-18 后，NK 细胞的抗病毒活性及其 IFN-γ 的产生减少，白细胞介素-18 受炎症小体调节。这些发现表明单核细胞在 NK 细胞激活中起作用。与对照单核细胞相比，慢性 HCV 感染患者的单核细胞 TNF-α 介导的（直接）和 NK 细胞介导的（间接）抗病毒作用降低。对照单核细胞增加了慢性 HCV 感染患者 NK 细胞的抗病毒作用及其 IFN-γ 的产生。
结论
单核细胞感知含有复制 HCV 的细胞，并通过炎症小体产生白细胞介素-18 和激活 NK 细胞来作出反应。慢性 HCV 感染患者的单核细胞功能降低，减弱了 NK 细胞 IFN-γ 介导的反应。
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