Early E-selectin, VCAM-1, ICAM-1, and late major histocompatibility complex antigen induction on human endothelial cells by flavivirus and comodulation of adhesion molecule expression by immune cytokines

Expression of E-selectin (ELAM-1, CD62E) on human umbilical vein endothelial cells significantly increased 30 min postinfection with the flavivirus West Nile virus (WNV), was maximal by 2 h postinfection, and declined to baseline levels within 24 h. Expression of ICAM-1 (CD54) and VCAM-1 (CD106) was significantly increased by 2 h and maximal at 4 h after infection. P-selectin (CD62P) expression was unaffected by WNV. Upregulation occurred earlier than that caused by tumor necrosis factor alpha (TNF-α) or interleukin 1 (IL-1) and could not be inhibited by neutralizing TNF-α, IL- α, or alpha/beta interferon (IFN-α/β) antibodies, suggesting a direct, virus-mediated phenomenon. TNF-α significantly enhanced WNV-induced increases in E-selectin, P-selectin, ICAM-1, and VCAM-1 expression, while IFN-γ enhanced WNV-induced ICAM-1 expression. In contrast, IL-4 abrogated WNV-induced E-selectin expression increases but acted in synergy with WNV to increase P-selectin and VCAM-1 expression. WNV increased the expression of class I and II major histocompatibility complex antigens (MHC-I and MHC-II, respectively) at 24 and 72 h, respectively. IFN-γ, TNF-α, or IL-1 acted in synergy with WNV to produce greater increases in MHC-I expression than WNV or cytokines alone, while IFN-α/β or IL-4 had no effect. MHC-II induction in cytokine-treated, WNV-infected cells was similar to that caused by cytokines alone. Neutralizing IFN-α/β antibody inhibited WNV-induced MHC-I expression by 30% at 24 h and by 100% by 72 h. The differential kinetics of modulation suggest sequential adhesion of leukocyte subpopulations to infected endothelial cells, which may be important in initial viral spread in vivo.