Wasmuth Hermann E, Zaldivar Mirko Moreno, Berres Marie-Luise, Werth Alexa, Scholten David, Hillebrandt Sonja, Tacke Frank, Schmitz Petra, Dahl Edgar, Wiederholt Tonio, Hellerbrand Claus, Berg Thomas, Weiskirchen Ralf, Trautwein Christian, Lammert Frank
Medical Department III, University Hospital Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany.
J Hepatol. 2008 Feb;48(2):208-15. doi: 10.1016/j.jhep.2007.09.008. Epub 2007 Nov 20.
BACKGROUND/AIMS: The chemokine receptor CX3CR1 and its specific ligand fractalkine (CX3CL1) are known to modulate inflammatory and fibroproliferative diseases. Here we investigate the role of CX3CR1/fractalkine in HCV-induced liver fibrosis.
A genotype analysis of CX3CR1 variants was performed in 211 HCV-infected patients. Hepatic expression of CX3CR1 was studied in HCV-infected livers and isolated liver cell populations by RT-PCR and immunohistochemistry. The effects of fractalkine on mRNA expression of profibrogenic genes were determined in isolated hepatic stellate cells (HSC) and CX3CR1 genotypes were related to intrahepatic TIMP-1 mRNA levels.
The intrahepatic mRNA expression of CX3CR1 correlates with the stage of HCV-induced liver fibrosis (P=0.03). The CX3CR1 coding variant V249I is associated with advanced liver fibrosis, independent of the T280M variant (P=0.009). CX3CR1 is present on primary HSC and fractalkine leads to a suppression of tissue inhibitor of metalloproteinase (TIMP)-1 mRNA in HSC (P=0.03). Furthermore, CX3CR1 genotypes are associated with TIMP-1 mRNA expression in HCV-infected liver (P=0.03).
The results identify the fractalkine receptor CX3CR1 as susceptibility a gene for hepatic fibrosis in HCV infection. The modulation of TIMP-1 expression by fractalkine and CX3CR1 genotypes provides functional support for the observed genotype-phenotype association.
背景/目的：已知趋化因子受体CX3CR1及其特异性配体fractalkine（CX3CL1）可调节炎症和纤维增殖性疾病。在此，我们研究CX3CR1/fractalkine在丙型肝炎病毒（HCV）诱导的肝纤维化中的作用。
对211例HCV感染患者进行CX3CR1变异体的基因型分析。通过逆转录聚合酶链反应（RT-PCR）和免疫组织化学研究HCV感染肝脏及分离的肝细胞群体中CX3CR1的肝内表达。在分离的肝星状细胞（HSC）中测定fractalkine对促纤维化基因mRNA表达的影响，并将CX3CR1基因型与肝内金属蛋白酶组织抑制剂1（TIMP-1）mRNA水平相关联。
CX3CR1的肝内mRNA表达与HCV诱导的肝纤维化阶段相关（P = 0.03）。CX3CR1编码变异体V249I与晚期肝纤维化相关，独立于T280M变异体（P = 0.009）。CX3CR1存在于原代HSC上，fractalkine可导致HSC中金属蛋白酶组织抑制剂（TIMP）-1 mRNA的表达受到抑制（P = 0.03）。此外，CX3CR1基因型与HCV感染肝脏中TIMP-1 mRNA表达相关（P = 0.03）。
结果确定趋化因子受体CX3CR1是HCV感染中肝纤维化的一个易感基因。fractalkine和CX3CR1基因型对TIMP-1表达的调节为观察到的基因型-表型关联提供了功能支持。
