Human cytomegalovirus binding to human monocytes induces immunoregulatory gene expression.
Human cytomegalovirus binding to human monocytes induces immunoregulatory gene expression.
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DOI：
10.4049/jimmunol.162.8.4806
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发表时间：
1999-04
影响因子：
4.4
通讯作者：
A. Yurochko;E. Huang
中科院分区：
文献类型：
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作者：
A. Yurochko;E. Huang
为了继续我们对人巨细胞病毒(HCMV)感染后发生的细胞事件的研究，我们专注于病毒与人单核细胞结合后细胞激活的调节。首先，我们发现病毒结合在未激活的单核细胞中诱导了一些免疫调节基因(IL-1β、A20、NF-kappaB-p105/p50和IkappaBalpha)，而针对主要HCMV糖蛋白的抗体Gb(UL55)和Gh(UL75)抑制了这些基因的诱导。接下来，我们证明了这些病毒配体在与其相应的细胞受体结合后，直接上调了单核细胞基因的表达。然后，我们研究了HCMV结合是否也导致了细胞因子的翻译和分泌。结果表明，人巨细胞病毒与单核细胞结合后可产生和释放IL-1β蛋白。由于这些诱导基因产物在其启动子区域具有核因子-kappaB位点，我们接下来检查是否存在核内核因子-kappaB水平的上调。这些实验表明，事实上，在病毒结合或纯化的病毒配体结合后，核转录因子-kappaB被转移到细胞核。IkappaBalpha水平的变化与核因子-kappaB易位的变化相关。最后，我们证明了p38激酶活性在IL-1β的产生中起核心作用，并且在感染后迅速上调。这些结果支持我们的假设，即HCMV启动了一条导致单核细胞活化的信号转导途径，并明确了一种潜在的机制，即单核细胞感染HCMV可导致深刻的发病机制，特别是在慢性炎症性疾病中。
To continue our investigation of the cellular events that occur following human CMV (HCMV) infection, we focused on the regulation of cellular activation following viral binding to human monocytes. First, we showed that viral binding induced a number of immunoregulatory genes (IL-1beta, A20, NF-kappaB-p105/p50, and IkappaBalpha) in unactivated monocytes and that neutralizing Abs to the major HCMV glycoproteins, gB (UL55) and gH (UL75), inhibited the induction of these genes. Next, we demonstrated that these viral ligands directly up-regulated monocyte gene expression upon their binding to their appropriate cellular receptors. We then investigated if HCMV binding also resulted in the translation and secretion of cytokines. Our results showed that HCMV binding to monocytes resulted in the production and release of IL-1beta protein. Because these induced gene products have NF-kappaB sites in their promoter regions, we next examined whether there was an up-regulation of nuclear NF-kappaB levels. These experiments showed that, in fact, NF-kappaB was translocated to the nucleus following viral binding or purified viral ligand binding. Changes in IkappaBalpha levels correlated with the changes in NF-kappaB translocation. Lastly, we demonstrated that p38 kinase activity played a central role in IL-1beta production and that it was rapidly up-regulated following infection. These results support our hypothesis that HCMV initiates a signal transduction pathway that leads to monocyte activation and pinpoints a potential mechanism whereby HCMV infection of monocytes can result in profound pathogenesis, especially in chronic inflammatory-type conditions.