Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
J Hepatol. 2010 Sep;53(3):424-30. doi: 10.1016/j.jhep.2010.03.018. Epub 2010 May 25.
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.
Peripheral blood mononuclear cells were obtained from patients with CHC and healthy subjects (HS) as controls.
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.
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.
自然杀伤 (NK) 细胞在针对病毒感染的免疫反应中发挥重要作用。干扰素 (IFN)-α 是治疗丙型肝炎病毒 (HCV) 感染的重要组成部分，可调节 NK 细胞的功能。然而，慢性 HCV 感染 (CHC) 如何改变 NK 细胞内 IFN-α 信号仍不清楚。我们研究了 CHC 患者 NK 细胞中的 IFN-α 信号。
从 CHC 患者和健康受试者 (HS) 中获得外周血单核细胞。
CHC 患者 NK 细胞中信号转导和转录激活因子 (STAT) 1 的表达水平明显高于 HS。NK 细胞中 IFN-α 刺激的 STAT1 磷酸化水平明显高于 HS，而 STAT4 的磷酸化水平明显低于 HS。这些 STAT1 和 STAT4 的磷酸化水平分别与 NK 细胞中的 STAT1 水平呈正相关和负相关。抑制细胞因子信号转导 1 的信使 RNA 水平在 CHC 患者的 NK 细胞中明显高于 HS，这是磷酸化 STAT1 的下游基因，而 IFN-γ的信使 RNA 水平，这是磷酸化 STAT4 的下游基因，明显低于 HS。
这些结果表明 CHC 患者 NK 细胞中的 IFN-α 信号发生改变，表明这种改变与 HCV 感染的持续存在和对 IFN-α 治疗的耐药性有关。
