Ribavirin inhibits DNA, RNA, and protein synthesis in PHA-stimulated human peripheral blood mononuclear cells:: Possible explanation for therapeutic efficacy in patients with chronic HCV infection
Ribavirin inhibits DNA, RNA, and protein synthesis in PHA-stimulated human peripheral blood mononuclear cells:: Possible explanation for therapeutic efficacy in patients with chronic HCV infection
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DOI：
10.1002/jmv.10264
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发表时间：
2003-01-01
影响因子：
12.7
通讯作者：
Ramadori, G
中科院分区：
文献类型：
--
作者：
Meier, V;Bürger, E;Ramadori, G
治疗慢性HCV感染的患者的选择是IFN-α和利巴韦林的组合。利巴韦林单药治疗导致临床和组织学改善，但其确切的作用机制尚不清楚。因此，利巴韦林对炎性细胞因子的合成和刺激的外周血单核细胞（PBMC）的凋亡的影响进行了研究。从HCV感染患者和健康志愿者的血液中分离PBMC。用酶联免疫吸附试验（ELISA）研究利巴韦林对未经刺激和经植物血凝素（PHA）刺激的PBMC上清液中IFN-γ和IL-1 β释放的影响。通过测量H-3-胸苷、H-3-尿苷和H-3-亮氨酸掺入细胞大分子中来分析对总DNA、RNA和蛋白质合成的影响。利巴韦林导致PHA刺激的PBMC上清液中IFN-γ的剂量依赖性降低，但IL-1 β的释放增加。与此同时，PHA刺激的PBMC培养物中总DNA、RNA和蛋白质合成的剂量依赖性降低被证明。这些影响可以通过添加等摩尔量的鸟苷来补偿。PBMCs培养物中凋亡的CD 45+和CD 14+细胞的比率以剂量依赖性方式增加。我们的数据表明，对慢性HCV感染患者给予利巴韦林可能导致促炎细胞因子（例如，IFN-γ）通过抑制总DNA-、RNA-和蛋白质-合成以及通过诱导炎性浸润细胞中的细胞凋亡。病毒唑还可影响肝细胞中病毒颗粒的合成。(C)2003 Wiley-Liss，Inc.
The treatment of choice for patients infected chronically with HCV is the combination of IFN-alpha and ribavirin. Monotherapy with ribavirin leads to a clinical and histological improvement, but its exact mechanism of action is unknown. Therefore, the effect of ribavirin on synthesis of inflammatory cytokines and on apoptosis in stimulated peripheral blood mononuclear cells (PBMCs) was investigated. PBMCs were isolated from the blood of HCV infected patients and from healthy volunteers. The effect of ribavirin on IFN-gamma and IL-1beta release in the supernatant of unstimulated and phytohemagglutinin (PHA) stimulated PBMCs was investigated by enzyme linked immunosorbent assay (ELISA). The effect on total DNA, RNA, and protein synthesis was analyzed by measurement of H-3-thymidine H-3-uridine and H-3-leucine incorporation into cellular macromolecules. Ribavirin led to a dose-dependent decrease of the IFN-gamma but an increase of IL-1beta release into the supernatant of PHA-stimulated PBMCs. At the same time, a dose-dependent decrease of total DNA, RNA, and protein synthesis in cultures of PHA-stimulated PBMCs was demonstrated. These effects could be compensated by the addition of equimolar amounts of guanosine. The rate of apoptotic CD45+ and CD14+ cells in PBMCs cultures increased in a dose-dependent manner. Our data suggest that ribavirin administration to chronically HCV-infected patients could lead to a decrease of the synthesis of proinflammatory cytokines (e.g., IFN-gamma) by an inhibition of total DNA-, RNA-, and protein-synthesis and by induction of apoptosis in the cells of the inflammatory infiltrate. Furthermore, ribavirin could influence the synthesis of viral particles in the hepatocytes. (C) 2003 Wiley-Liss, Inc.