Cytomegalovirus infection of vascular cells induces expression of pro-inflammatory adhesion molecules by paracrine action of secreted interleukin-1 beta

Background. Infection with human cytomegalovirus (HCMV) has been associated with vascular disease processes such as vascular allograft rejection, tran splantation vasculopathy, restenosis after angioplasty, and native atherosc lerosis. 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 quantif ied 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 increa sed by >200%. On hvSMC, intercellular adhesion molecule-1 surface expressio n induced de novo, although vascular cell adhesion molecule-1 and E-selecti n were not changed. Expression of major histocompatibility complex (MHC) cl ass II, lymphocyte-function associated antigen 3 (LFA-3; CD58), and CD40 wa s not altered by HCMV infection in either cell type. In partially infected cultures, up-regulation of surface molecules also occurred on noninfected c ells, suggesting a paracrine mechanism via a soluble factor. Expression of surface molecules could be enhanced in noninfected HUVEC and hvSMC by incub ation with virus-free conditioned supernatant from HCMV-infected cells or b y coincubation in transwells with infected cells. The responsible agent cou ld be identified as IL- interleukin- (IL) 1 beta by detection of de novo se cretion of IL-1 beta by HCMV-infected cells and by prevention of adhesion m olecule up-regulation after addition of an IL-1-converting enzyme inhibitor or IL-1 receptor antagonist. Surface molecule up-regulation could be suppr essed by UV inactivation of virus, but not by treatment of cell cultures wi th inhibitors of viral replication (ganciclovir). Conclusion. We propose that HCMV infection induces IL-1 beta release and su bsequent up-regulation of pro-inflammatory adhesion molecules on noninfecte d neighboring cells through a paracrine mechanism. This may lead to local p otentiation of the inflammatory effects of HCMV infection, not amenable to current therapeutic antiviral strategies.