Cytomegalovirus infection of vascular cells induces expression of pro-inflammatory adhesion molecules by paracrine action of secreted interleukin-1β
Cytomegalovirus infection of vascular cells induces expression of pro-inflammatory adhesion molecules by paracrine action of secreted interleukin-1β
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DOI：
10.1097/00007890-200003270-00022
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发表时间：
2000-03-27
期刊：
影响因子：
6.2
通讯作者：
Schönrich, G
中科院分区：
文献类型：
--
作者：
Dengler, TJ;Raftery, MJ;Schönrich, G
背景。人类巨细胞病毒（HCMV）感染与血管疾病过程相关，如血管异体移植排斥反应、移植血管病变、血管成形术后再狭窄和原生动脉粥样硬化。为了阐明其潜在的病理机制，研究了急性HCMV感染对人脐静脉内皮细胞（HUVEC）和人血管平滑肌细胞（hvSMC）促炎粘附分子表达的影响。方法与结果。用临床HCMV菌株体外感染细胞，通过组织学和流式细胞术分析，定量观察细胞粘附分子表达的变化。在HUVEC上，血管细胞黏附分子-1和e-选择素的表面表达在HCMV感染下从头诱导，细胞间黏附分子-1的表达增加了bb0 ~ 200%。在hvSMC中，细胞间粘附分子-1表面表达诱导新生，但血管细胞粘附分子-1和e-选择素没有改变。主要组织相容性复合体（MHC） II类、淋巴细胞功能相关抗原3 （LFA-3; CD58）和CD40的表达均未因HCMV感染而改变。在部分感染的培养中，表面分子的上调也发生在未感染的细胞上，表明通过可溶性因子的旁分泌机制。在未感染的HUVEC和hvSMC中，通过与hcmv感染细胞的无病毒条件上清孵育或与感染细胞共孵育，可以增强表面分子的表达。通过检测感染hcmv的细胞重新分泌IL-1 β和添加IL-1转换酶抑制剂或IL-1受体拮抗剂后阻止粘附分子上调，可以确定其为IL-白细胞介素- (IL) 1 β。紫外线灭活病毒可以抑制表面分子的上调，但用病毒复制抑制剂（更昔洛韦）处理细胞培养物不能抑制表面分子的上调。我们提出HCMV感染通过旁分泌机制诱导IL-1 β释放并随后在未感染的邻近细胞上上调促炎粘附分子。这可能导致HCMV感染的局部炎症效应增强，不适合目前的治疗性抗病毒策略。
Background. Infection with human cytomegalovirus (HCMV) has been associated with vascular disease processes such as vascular allograft rejection, transplantation vasculopathy, restenosis after angioplasty, and native atherosclerosis. To elucidate underlying pathomechanisms, the effect of acute HCMV infection on the expression of pro-inflammatory adhesion molecules on human umbilical vein endothelial cells (HUVEC) and human vascular smooth muscle cells (hvSMC) was examined.Methods and Results. Cells were infected in vitro with clinical strains of HCMV and the resulting changes in adhesion molecule expression were quantified by histology and flow cytometric analysis. On HUVEC, surface expression of vascular cell adhesion molecule-1 and E-selectin was induced de novo on HCMV infection and intercellular adhesion molecule-1 expression was increased by >200%. On hvSMC, intercellular adhesion molecule-1 surface expression induced de novo, although vascular cell adhesion molecule-1 and E-selectin were not changed. Expression of major histocompatibility complex (MHC) class II, lymphocyte-function associated antigen 3 (LFA-3; CD58), and CD40 was not altered by HCMV infection in either cell type. In partially infected cultures, up-regulation of surface molecules also occurred on noninfected cells, suggesting a paracrine mechanism via a soluble factor. Expression of surface molecules could be enhanced in noninfected HUVEC and hvSMC by incubation with virus-free conditioned supernatant from HCMV-infected cells or by coincubation in transwells with infected cells. The responsible agent could be identified as IL- interleukin- (IL) 1 beta by detection of de novo secretion of IL-1 beta by HCMV-infected cells and by prevention of adhesion molecule up-regulation after addition of an IL-1-converting enzyme inhibitor or IL-1 receptor antagonist. Surface molecule up-regulation could be suppressed by UV inactivation of virus, but not by treatment of cell cultures with inhibitors of viral replication (ganciclovir).Conclusion. We propose that HCMV infection induces IL-1 beta release and subsequent up-regulation of pro-inflammatory adhesion molecules on noninfected neighboring cells through a paracrine mechanism. This may lead to local potentiation of the inflammatory effects of HCMV infection, not amenable to current therapeutic antiviral strategies.