Department of Gastroenterology and Hepatology, University Hospital of Essen, Hufelandstr. 55, 45122 Essen, Germany.
J Hepatol. 2009 Dec;51(6):1037-45. doi: 10.1016/j.jhep.2009.06.020. Epub 2009 Jul 29.
BACKGROUND/AIMS: While hepatic stellate cells (HSC) are known to be key mediators of liver fibrosis, only little is known about their functional role in the innate immune system of the liver.
To address this question, murine HSC were isolated from livers of C57BL/6J mice and human HSC were isolated from liver samples obtained from resections and liver explants. HSC were stimulated with Toll-like receptor (TLR) 1-9 ligands for 20 h. Supernatants were harvested and used in virus protection assays (encephalomyocarditis virus, EMCV) as well as in human and murine hepatitis C virus (HCV) replicon systems. Expression of interferon (IFN), retinoic acid-inducible gene-I (RIG-I), and interferon-stimulated genes (ISGs) was assessed by quantitative reverse transcription polymerase chain reaction.
While all TLRs were detectable in HSC, in murine HSC only TLR 3 and -4 agonists could induce cytokines that had an antiviral effect upon EMCV and HCV replication. IFN-beta was the main cytokine mediating the antiviral activity of TLR 3-stimulated HSC whereas other cytokines of undefined nature were involved in TLR 4-mediated antiviral effects. In human HSC, only TLR 3 stimulation led to production of antiviral cytokines. The antiviral effect was related to the up-regulation of ISGs and RIG-I in target cells.
These data demonstrate that murine and human HSC have as yet unrecognized antiviral properties when activated through the TLR-system and TLR 3/HCV in particular. This sheds new light on their role in the innate immune system of the liver and their participation in the control of HCV replication.
背景/目的：已知肝星状细胞（HSC）是肝纤维化的主要介导者，但它们在肝脏固有免疫系统中的功能作用知之甚少。
为了解决这个问题，从 C57BL/6J 小鼠肝脏中分离出鼠 HSC，并从切除和肝外植体获得的肝样本中分离出人 HSC。用 Toll 样受体（TLR）1-9 配体刺激 HSC 20 小时。收集上清液并用于病毒保护测定（脑炎心肌炎病毒，EMCV）以及人源和鼠源丙型肝炎病毒（HCV）复制子系统。通过定量逆转录聚合酶链反应评估干扰素（IFN）、视黄酸诱导基因-I（RIG-I）和干扰素刺激基因（ISGs）的表达。
虽然 HSC 中均可检测到所有 TLR，但在鼠 HSC 中，只有 TLR 3 和 -4 激动剂才能诱导具有抗 EMCV 和 HCV 复制作用的细胞因子。IFN-β是介导 TLR 3 刺激的 HSC 抗病毒活性的主要细胞因子，而其他性质不明的细胞因子参与 TLR 4 介导的抗病毒作用。在人 HSC 中，只有 TLR 3 刺激才能产生抗病毒细胞因子。抗病毒作用与靶细胞中 ISGs 和 RIG-I 的上调有关。
这些数据表明，当通过 TLR 系统激活时，鼠和人 HSC 具有尚未被认识到的抗病毒特性，特别是 TLR 3/HCV。这为它们在肝脏固有免疫系统中的作用及其参与 HCV 复制的控制提供了新的视角。
