Mühlbauer Marcus, Bosserhoff Anja K, Hartmann Arndt, Thasler Wolfgang E, Weiss Thomas S, Herfarth Hans, Lock Guntram, Schölmerich Jürgen, Hellerbrand Claus
Department of Internal Medicine I, University of Regensburg, Regensburg, Germany.
Gastroenterology. 2003 Oct;125(4):1085-93. doi: 10.1016/s0016-5085(03)01213-7.
Factors influencing the progression of chronic hepatitis C virus (HCV) infection are poorly understood. Monocyte chemotactic protein-1 (MCP-1) is a potent chemokine, and its hepatic expression is up-regulated during chronic HCV infection mainly in activated hepatic stellate cells (HSC). In this study, we investigated the correlation of the functional -2518 MCP-1 promoter polymorphism with hepatic MCP-1 expression and the disease outcome in patients with HCV.
MCP-1 genotyping was performed in 206 patients and 139 healthy controls. Hepatic MCP-1 messenger RNA (mRNA) expression was quantified by real-time PCR in 58 HCV patients. Cytokine-induced MCP-1 secretion of activated human HSC (n = 13) was determined by enzyme-linked immunosorbent assay (ELISA). Mobility-shift assays were performed using probes corresponding to the MCP-1 promoter sequence (-2511 to -2528) with or without the A to G mutation at -2518.
Frequency of MCP-1 genotypes did not differ between HCV patients and controls. However, carriers of the G allele were significantly more frequent in HCV patients with more advanced fibrosis and severe inflammation. In accordance, hepatic MCP-1 mRNA levels were significantly higher in patients with more advanced fibrosis and in patients carrying the G allele. Furthermore, cytokine-induced MCP-1 secretion of HSC isolated from carriers of the G allele was significantly higher, and there was binding activity in nuclear extracts from activated HSC specifically to the G allele, providing a potential mechanism for the differences seen.
Inheritance of the -2518 MCP-1 G allele, which appears to affect hepatic MCP-1 expression, may predispose HCV patients to more severe hepatic inflammation and fibrosis.
影响慢性丙型肝炎病毒（HCV）感染进展的因素尚不清楚。单核细胞趋化蛋白-1（MCP-1）是一种强效趋化因子，在慢性HCV感染期间，其肝脏表达主要在活化的肝星状细胞（HSC）中上调。在本研究中，我们调查了功能性-2518 MCP-1启动子多态性与肝脏MCP-1表达以及HCV患者疾病转归之间的相关性。
对206例患者和139例健康对照进行MCP-1基因分型。通过实时PCR对58例HCV患者的肝脏MCP-1信使核糖核酸（mRNA）表达进行定量。采用酶联免疫吸附测定（ELISA）法测定细胞因子诱导的活化人HSC（n = 13）分泌的MCP-1。使用与MCP-1启动子序列（-2511至-2528）相对应的探针进行迁移率变动分析，该序列在-2518处有或没有A到G的突变。
HCV患者和对照之间MCP-1基因型频率没有差异。然而，在纤维化更严重和炎症更严重的HCV患者中，G等位基因携带者明显更常见。相应地，在纤维化更严重的患者和携带G等位基因的患者中，肝脏MCP-1 mRNA水平显著更高。此外，从G等位基因携带者分离的HSC中细胞因子诱导的MCP-1分泌显著更高，并且活化HSC的核提取物中存在与G等位基因特异性结合的活性，这为观察到的差异提供了潜在机制。
-2518 MCP-1 G等位基因的遗传似乎会影响肝脏MCP-1表达，可能使HCV患者更容易发生更严重的肝脏炎症和纤维化。
