IFN-gamma inhibits double-stranded RNA-induced E-selectin expression in human endothelial cells

IFN-gamma plays a role in immune regulatory functions as well as in viral defense. We show in this study that IFN-gamma treatment down-regulates the induction by a viral mimetic, polyinosinic-polycytidylic acid (poly(I:C)), of the endothelial cell-specific leukocyte adhesion protein, E-selectin. The inhibitory effect of IFN-gamma on poly(I:C)-induced E-selectin was concentration and time dependent and was specific for dsRNA, in that the induction of E-selectin by TNF-alpha, IL-1 beta, thrombin, or LPS was not inhibited significantly by this pretreatment. IFN-gamma pretreatment reduced poly(I:C)-induced E-selectin mRNA in a protein synthesis-independent manner. Poly(I:C)-induced E-selectin mRNA t1/2 was reduced slightly by IFN-gamma treatment, while the message for VCAM-1 was stabilized. Transient transfection of endothelial cells with an E-selectin promoter-driven reporter gene construct revealed that poly(I:C) stimulation of E-selectin promoter activity was decreased significantly by IFN-gamma pretreatment. Poly(I:C)-induced nuclear factor-kappa B activation following IFN-gamma pretreatment was unaffected, as shown by electrophoretic mobility shift analysis. These results indicate a novel role for IFN-gamma in the regulation of E-selectin gene expression in response to dsRNA by a transcriptional mechanism independent of nuclear factor-kappa B, as well as by a minor decrease in message stability.