Altered interferon-α-signaling in natural killer cells from patients with chronic hepatitis C virus infection
Altered interferon-α-signaling in natural killer cells from patients with chronic hepatitis C virus infection
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DOI：
10.1016/j.jhep.2010.03.018
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发表时间：
2010-09-01
影响因子：
25.7
通讯作者：
Hayashi, Norio
中科院分区：
文献类型：
--
作者：
Miyagi, Takuya;Takehara, Tetsuo;Hayashi, Norio
背景与目的：自然杀伤（NK）细胞在抗病毒感染的免疫应答中起重要作用。干扰素（IFN）-α是治疗丙型肝炎病毒（HCV）感染的重要成分，调节NK细胞功能。然而，慢性HCV感染（CHC）如何改变NK细胞中的细胞内IFN-α信号传导仍然不清楚。方法：收集CHC患者外周血单个核细胞（PBMC），以健康人（HS）为对照，检测CHC患者NK细胞中IFN-α信号转导子和转录激活子（STAT）1的表达水平，结果：CHC患者NK细胞中IFN-α信号转导子和转录激活子1的表达水平明显高于HS患者。IFN-α刺激后CHC患者NK细胞中STAT 1的磷酸化水平显著高于HS患者，而STAT 4的磷酸化水平显著低于HS患者，且STAT 1和STAT 4的磷酸化水平分别与NK细胞中的STAT 1水平呈正相关和负相关。IFN-α诱导的细胞因子信号传导抑制因子1（磷酸化STAT 1的下游基因）的信使RNA水平在CHC患者的NK细胞中明显高于HS患者的NK细胞，而IFN-γ（磷酸化STAT 4的下游基因）的信使RNA水平明显较低。这些结果表明CHC患者NK细胞中IFN-α信号传导的改变，表明这种改变与HCV感染的持续性和对IFN-α治疗的耐药性有关。(C)2010年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Natural killer (NK) cells play an important role in the immune response against virus infection. Interferon (IFN)-alpha, an essential component in therapy against hepatitis C virus (HCV) infection, regulates NK cell function. However, it remains obscure how chronic HCV infection (CHC) modifies intracellular IFN-alpha signaling in NK cells. We investigated IFN-alpha signaling in NK cells in patients with CHC.Methods: Peripheral blood mononuclear cells were obtained from patients with CHC and healthy subjects (HS) as controls.Results: The expression level of signal transducer and activator of transcription (STAT) 1, a key molecule of IFN-alpha signaling, was clearly higher in NK cells from the CHC patients than in those from HS. The phosphorylation level of STAT1 with IFN-alpha stimulation was significantly greater in NK cells from the CHC patients than in those from the HS, while that of STAT4 was significantly less. These phosphorylation levels of STAT1 and STAT4 positively and negatively correlated with the STAT1 level in NK cells, respectively. The IFN-alpha induced messenger RNA level of the suppressor of cytokine signaling 1, which is a downstream gene of phosphorylated-STAT1, was clearly greater in NK cells from the CHC patients than in those from the HS, while that of IFN-gamma, which is a downstream gene of phosphorylated-STAT4, was clearly lower.Conclusions: These results indicate altered IFN-alpha signaling in NK cells in CHC patients, suggesting that this alteration is associated with the persistence of HCV infection and resistance to IFN-alpha therapy. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.