El Mjiyad Nadia, Bontems Sébastien, Gloire Geoffrey, Horion Julie, Vandevenne Patricia, Dejardin Emmanuel, Piette Jacques, Sadzot-Delvaux Catherine
GIGA-Research, Virology and Immunology Unit, GIGA B34, University of Liège, B-4000 Liège, Belgium.
J Virol. 2007 Dec;81(23):13092-104. doi: 10.1128/JVI.01378-07. Epub 2007 Sep 12.
Intercellular adhesion molecule 1 (ICAM-1) expression is down-regulated in the center of cutaneous varicella lesions despite the expression of proinflammatory cytokines such as gamma interferon and tumor necrosis factor alpha (TNF-alpha). To study the molecular basis of this down-regulation, the ICAM-1 induction of TNF-alpha was analyzed in varicella-zoster virus (VZV)-infected melanoma cells (MeWo), leading to the following observations: (i) VZV inhibits the stimulation of icam-1 mRNA synthesis; (ii) despite VZV-induced nuclear translocation of p65, p52, and c-Rel, p50 does not translocate in response to TNF-alpha; (iii) the nuclear p65 present in VZV-infected cells is no longer associated with p50 and is unable to bind the proximal NF-kappaB site of the icam-1 promoter, despite an increased acetylation and accessibility of the promoter in response to TNF-alpha; and (iv) VZV induces the nuclear accumulation of the NF-kappaB inhibitor p100. VZV also inhibits icam-1 stimulation of TNF-alpha by strongly reducing NF-kappaB nuclear translocation in MRC5 fibroblasts. Taken together, these data show that VZV interferes with several aspects of the immune response by inhibiting NF-kappaB binding and the expression of target genes. Targeting NF-kappaB activation, which plays a central role in innate and adaptive immune responses, leads to obvious advantages for the virus, particularly in melanocytes, which are a site of viral replication in the skin.
尽管在皮肤水痘病变中心存在γ干扰素和肿瘤坏死因子α（TNF-α）等促炎细胞因子的表达，但细胞间黏附分子1（ICAM-1）的表达却下调。为了研究这种下调的分子基础，我们分析了水痘带状疱疹病毒（VZV）感染的黑色素瘤细胞（MeWo）中TNF-α对ICAM-1的诱导作用，得出以下观察结果：（i）VZV抑制icam-1 mRNA合成的刺激；（ii）尽管VZV诱导p65、p52和c-Rel发生核转位，但p50不会因TNF-α而发生核转位；（iii）VZV感染细胞中存在的核p65不再与p50结合，尽管启动子因TNF-α而乙酰化增加且可及性增强，但仍无法结合icam-1启动子的近端NF-κB位点；（iv）VZV诱导NF-κB抑制剂p100发生核积累。VZV还通过强烈减少MRC5成纤维细胞中的NF-κB核转位来抑制TNF-α对icam-1的刺激。综上所述，这些数据表明VZV通过抑制NF-κB结合和靶基因表达来干扰免疫反应的多个方面。靶向在先天和适应性免疫反应中起核心作用的NF-κB激活，对病毒具有明显优势，特别是在黑色素细胞中，黑色素细胞是皮肤中病毒复制的位点。
