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.
Faruqi
T R
TR
Department of Cell Biology, Research Institute of The Cleveland Clinic Foundation, OH 44195, USA.
DiCorleto
P E
PE
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D019040:E-Selectin / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D012330:RNA, Double-Stranded / Q000494:pharmacology*
D019040:E-Selectin; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D007371:Interferon-gamma; D011070:Poly I-C