Dolganiuc Angela, Kodys Karen, Kopasz Andrea, Marshall Christopher, Do Twan, Romics Laszlo, Mandrekar Pranoti, Zapp Maria, Szabo Gyongyi
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
J Immunol. 2003 Jun 1;170(11):5615-24. doi: 10.4049/jimmunol.170.11.5615.
Antiviral immunity requires recognition of viral pathogens and activation of cytotoxic and Th cells by innate immune cells. In this study, we demonstrate that hepatitis C virus (HCV) core and nonstructural protein 3 (NS3), but not envelope 2 proteins (E2), activate monocytes and myeloid dendritic cells (DCs) and partially reproduce abnormalities found in chronic HCV infection. HCV core or NS3 (not E2) triggered inflammatory cytokine mRNA and TNF-alpha production in monocytes. Degradation of I-kappa B alpha suggested involvement of NF-kappa B activation. HCV core and NS3 induced production of the anti-inflammatory cytokine, IL-10. Both monocyte TNF-alpha and IL-10 levels were higher upon HCV core and NS3 protein stimulation in HCV-infected patients than in normals. HCV core and NS3 (not E2) inhibited differentiation and allostimulatory capacity of immature DCs similar to defects in HCV infection. This was associated with elevated IL-10 and decreased IL-2 levels during T cell proliferation. Increased IL-10 was produced by HCV patients' DCs and by core- or NS3-treated normal DCs, while IL-12 was decreased only in HCV DCs. Addition of anti-IL-10 Ab, not IL-12, ameliorated T cell proliferation with HCV core- or NS3-treated DCs. Reduced allostimulatory capacity in HCV core- and NS3-treated immature DCs, but not in DCs of HCV patients, was reversed by LPS maturation, suggesting more complex DC defects in vivo than those mediated by core or NS3 proteins. Our results reveal that HCV core and NS3 proteins activate monocytes and inhibit DC differentiation in the absence of the intact virus and mediate some of the immunoinhibitory effects of HCV via IL-10 induction.
抗病毒免疫需要识别病毒病原体，并由天然免疫细胞激活细胞毒性T细胞和辅助性T细胞。在本研究中，我们证明丙型肝炎病毒（HCV）核心蛋白和非结构蛋白3（NS3），而非包膜蛋白2（E2），可激活单核细胞和髓样树突状细胞（DC），并部分重现慢性HCV感染中发现的异常情况。HCV核心蛋白或NS3（而非E2）可触发单核细胞中炎性细胞因子mRNA和肿瘤坏死因子-α（TNF-α）的产生。I-κBα的降解提示核因子-κB（NF-κB）激活的参与。HCV核心蛋白和NS3可诱导抗炎细胞因子白细胞介素-10（IL-10）的产生。在HCV感染患者中，HCV核心蛋白和NS3蛋白刺激后，单核细胞TNF-α和IL-10水平均高于正常人。HCV核心蛋白和NS3（而非E2）抑制未成熟DC的分化和同种异体刺激能力，类似于HCV感染中的缺陷。这与T细胞增殖过程中IL-10升高和IL-2水平降低有关。HCV患者的DC以及经核心蛋白或NS3处理后的正常DC均可产生更多的IL-10，而只有HCV患者的DC中IL-12水平降低。添加抗IL-10抗体（而非IL-12）可改善经HCV核心蛋白或NS3处理的DC对T细胞的增殖作用。经LPS成熟处理后，HCV核心蛋白和NS3处理的未成熟DC的同种异体刺激能力降低，但HCV患者的DC则无此现象，这表明体内DC的缺陷比核心蛋白或NS3蛋白介导的缺陷更为复杂。我们的研究结果表明，在无完整病毒的情况下，HCV核心蛋白和NS3蛋白可激活单核细胞并抑制DC分化，并通过诱导IL-10介导HCV的一些免疫抑制作用。
