Interferon-beta is a potent inducer of interferon regulatory factor-1/2-dependent IP-10/CXCL10 expression in primary human endothelial cells.

J Vasc Res 2007 13;44(1):51-60. Epub 2006 Dec 13.

Department of Neurology, Julius-Maximilians University, Josef-Schneider-Strasse 11, DE-97080 W├╝rzburg, Germany.

Most virus-infected cells release interferon-beta (IFN-beta) as a powerful inducer of antiviral defense. Endothelial cells tightly regulate local immune cell recruitment by expression of adhesion molecules and chemokines. Here, we studied the transcriptional regulation of IFN-beta-induced chemokine expression in primary human endothelial cells. IFN-beta moderately increased monocyte chemoattractant protein-1/CCL2 and potently raised IFN-gamma-inducible protein-10/CXCL10 mRNA steady-state levels and protein release, while no effect was detected on various other chemokines. As shown by transient transfections, induction of CXCL10 expression depends on an IFN-stimulated response element (ISRE) within the CXCL10 promoter. A double point mutation of the putative IFN regulatory factor (IRF)-1/2 binding site within this ISRE motif abolished IFN-beta-induced promoter activity. In electrophoretic mobility shift assays, this ISRE motif showed a basal IRF-2 and an IFN-beta-inducible IRF-1 and augmented IRF-2 binding. Furthermore, stimulation with IFN-beta induced a rapid nuclear translocation of signal transducer and activator of transcription 1 (STAT1) and STAT2 and their transient binding to a gamma-activated site within the CCL2 promoter. The kinetics of transient STAT1 binding to this gamma-activated site element correlated with the amount of Y701-phosphorylated nuclear STAT1, while S727-phosphorylated nuclear STAT1 remained stable over 24 h after stimulation. Therefore, IFN-beta potently induces endothelial chemokine expression at the transcriptional level.

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http://dx.doi.org/10.1159/000097977DOI Listing
February 2007
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