Hepatitis C Virus Induced Endothelial Inflammatory Response Depends on the Functional Expression of TNFα Receptor Subtype 2

In hepatitis C virus (HCV) infection, morbidity and mortality often result from extrahepatic disease manifestations. We provide evidence for a role of receptors of the innate immune system in virally induced inflammation of the endothelium in vitro and in vivo. Corresponding to the in vitro finding of an HCV-dependent induction of proinflammatory mediators in endothelial cells, mice treated with poly (I:C) exhibit a significant reduction in leukocyte rolling velocity, an increase in leukocyte adhesion to the vessel wall and an increased extravasation of leukocytes. HCV directly promotes activation, adhesion and infiltration of inflammatory cells into the vessel wall by activation of endothelial viral receptors. Poly (I:C) induces the expression of TLR3 in vivo and hereby allows for amplification of all of the aforementioned responses upon viral infection. Proinflammatory effects of viral RNA are specifically mediated by TLR3 and significantly enhanced by tumor necrosis factor alpha (TNFα). HCV-RNA induces the endothelial expression of TNFα and TNFα receptor subtype 2 and we provide evidence that leucocyte adhesion and transmigration in response to activation of viral RNA receptors seem to depend on expression of functional TNFR2. Our results demonstrate that endothelial cells actively participate in immune mediated vascular inflammation caused by viral infections.丙型肝炎病毒（HCV）感染所致的发病与死亡，常源于肝外疾病表现。本研究证实，先天免疫系统受体在体内外病毒诱导的内皮炎症中发挥了关键作用。与体外实验中HCV可诱导内皮细胞产生促炎介质的发现相符，经聚肌胞苷酸（poly(I:C)）处理的小鼠表现为白细胞滚动速度显著降低、白细胞黏附于血管壁的现象增多，以及白细胞外渗增加。HCV可通过激活内皮病毒受体，直接促进炎症细胞活化、黏附并浸润至血管壁。聚肌胞苷酸（poly(I:C)）可在体内诱导Toll样受体3（TLR3）的表达，从而在病毒感染时放大上述所有应答反应。病毒RNA的促炎效应由TLR3特异性介导，并可被肿瘤坏死因子α（TNFα）显著增强。HCV-RNA可诱导内皮细胞表达TNFα及肿瘤坏死因子受体2型（TNFR2）；本研究证实，针对病毒RNA受体激活所引发的白细胞黏附与跨内皮迁移过程，似乎依赖于功能性TNFR2的表达。本研究结果表明，内皮细胞可主动参与病毒感染引发的免疫介导性血管炎症。