Dengler T J, Raftery M J, Werle M, Zimmermann R, Schönrich G
Department of Cardiology, University of Heidelberg, Germany.
Transplantation. 2000 Mar 27;69(6):1160-8. doi: 10.1097/00007890-200003270-00022.
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.
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) 1beta by detection of de novo secretion of IL-1beta 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).
We propose that HCMV infection induces IL-1beta 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.
人巨细胞病毒（HCMV）感染与血管疾病进程相关，如血管移植排斥、移植血管病变、血管成形术后再狭窄以及原发性动脉粥样硬化。为阐明潜在的发病机制，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）上促炎黏附分子表达的影响。
用HCMV临床分离株体外感染细胞，通过组织学和流式细胞术分析对黏附分子表达的变化进行定量。在HUVEC上，HCMV感染后血管细胞黏附分子-1和E-选择素的表面表达从头诱导，细胞间黏附分子-1的表达增加超过200%。在hvSMC上，细胞间黏附分子-1的表面表达从头诱导，而血管细胞黏附分子-1和E-选择素未发生变化。在两种细胞类型中，HCMV感染均未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。在部分感染的培养物中，未感染细胞的表面分子也上调，提示通过可溶性因子的旁分泌机制。通过用来自HCMV感染细胞的无病毒条件上清液孵育或在Transwell中与感染细胞共孵育，可增强未感染的HUVEC和hvSMC表面分子的表达。通过检测HCMV感染细胞中IL-1β的从头分泌以及添加IL-1转换酶抑制剂或IL-1受体拮抗剂后黏附分子上调的预防，可将致病因子鉴定为白细胞介素-1β（IL-1β）。表面分子上调可通过病毒的紫外线灭活来抑制，但不能通过用病毒复制抑制剂（更昔洛韦）处理细胞培养物来抑制。
我们提出，HCMV感染通过旁分泌机制诱导IL-1β释放，随后未感染的邻近细胞上促炎黏附分子上调。这可能导致HCMV感染炎症效应的局部增强，而目前的治疗性抗病毒策略对此无效。
