Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
Gastroenterology. 2010 May;138(5):1875-84. doi: 10.1053/j.gastro.2010.02.004. Epub 2010 Feb 10.
BACKGROUND & AIMS: Corticosteroids are used as immunosuppressants in patients with autoimmune disorders and transplant recipients. However, these drugs worsen hepatitis C virus (HCV) recurrence after liver transplantation, suggesting that they may directly exacerbate HCV infection.
The influence of immunosuppressive drugs on HCV replication, assembly, and entry was assessed in Huh-7.5 cells and primary human hepatocytes using cell culture- and patient-derived HCV. Replication was quantified by immunofluorescence, luciferase assays, quantitative reverse-transcriptase polymerase chain reaction, or core enzyme-linked immunosorbent assays. Expression of HCV entry factors was evaluated by cell sorting and immunoblot analyses.
Glucocorticosteroids slightly reduced HCV RNA replication but increased efficiency of HCV entry by up to 10-fold. This was independent of HCV genotype but specific to HCV because vesicular stomatitis virus glycoprotein-dependent infection was not affected by these drugs. The increase in HCV entry was accompanied by up-regulation of messenger RNA and protein levels of occludin and the scavenger receptor class B type I-2 host cell proteins required for HCV infection; increase of entry by glucocorticosteroids was ablated by RU-486, an inhibitor of glucocorticosteroid signaling. Glucocorticosteroids increased propagation of cell culture-derived HCV approximately 5- to 10-fold in partially differentiated human hepatoma cells and increased infection of primary human hepatocytes by cell culture- and patient-derived HCV.
Glucocorticosteroides specifically increase HCV entry by up-regulating the cell entry factors occludin and scavenger receptor class B type I. Our data suggest that the potential effects of high-dose glucocorticosteroids on HCV infection in vivo may be due to increased HCV dissemination.
皮质类固醇被用作自身免疫性疾病患者和移植受者的免疫抑制剂。然而，这些药物会加重肝移植后丙型肝炎病毒（HCV）的复发，这表明它们可能直接加重 HCV 感染。
使用细胞培养和患者来源的 HCV 在 Huh-7.5 细胞和原代人肝细胞中评估免疫抑制剂对 HCV 复制、组装和进入的影响。通过免疫荧光、荧光素酶测定、定量逆转录聚合酶链反应或核心酶联免疫吸附测定来量化复制。通过细胞分选和免疫印迹分析评估 HCV 进入因子的表达。
糖皮质激素略微降低 HCV RNA 复制，但将 HCV 进入的效率提高多达 10 倍。这与 HCV 基因型无关，但与 HCV 特异性相关，因为水疱性口炎病毒糖蛋白依赖性感染不受这些药物影响。HCV 进入的增加伴随着 occludin 和需要 HCV 感染的清道夫受体类 B 型 I-2 宿主细胞蛋白的信使 RNA 和蛋白水平的上调；RU-486（一种糖皮质激素信号抑制剂）可消除糖皮质激素对 HCV 进入的增加。糖皮质激素在部分分化的人肝癌细胞中使细胞培养衍生的 HCV 大约增加 5-10 倍的复制，并增加细胞培养和患者衍生的 HCV 对原代人肝细胞的感染。
糖皮质激素通过上调细胞进入因子 occludin 和清道夫受体类 B 型 I 特异性增加 HCV 进入。我们的数据表明，高剂量糖皮质激素对体内 HCV 感染的潜在影响可能是由于 HCV 传播增加所致。
