Interferon-β Is a Potent Inducer of Interferon Regulatory Factor-1/2-Dependent IP-10/CXCL10 Expression in Primary Human Endothelial Cells

Abstract

Most virus-infected cells release interferon-β (IFN-β) 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-β-induced chemokine expression in primary human endothelial cells. IFN-β moderately increased monocyte chemoattractant protein-1/CCL2 and potently raised IFN-γ-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-β-induced promoter activity. In electrophoretic mobility shift assays, this ISRE motif showed a basal IRF-2 and an IFN-β-inducible IRF-1 and augmented IRF-2 binding. Furthermore, stimulation with IFN-β induced a rapid nuclear translocation of signal transducer and activator of transcription 1 (STAT1) and STAT2 and their transient binding to a γ-activated site within the CCL2 promoter. The kinetics of transient STAT1 binding to this γ-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-β potently induces endothelial chemokine expression at the transcriptional level.

Tissue Macrophages Suppress Viral Replication and Prevent Severe Immunopathology in an Interferon-I-Dependent Manner in Mice

“…The inability of hepatocytes to respond to IFN-I could be explained by the finding that hepatocytes failed to express significant levels of messenger RNA encoding IFNAR and downstream signaling molecules compared with macrophages. Liver endothelial cells are equipped with Toll-like receptors and are involved in the antiviral innate immune response, 34,35 including uptake of serum particles. 15 In addition to cytokine production, liver sinusoid endothelial cells show a strong antiviral response to IFN-I, 34,36 which could suppress virus replication 37 ; however, whether this is of benefit for a systemic virus infection remains to be studied.…”

Evaluation of Serum Levels of Chemokines during Interferon-β Treatment in Multiple Sclerosis Patients

“…[32] In addition, IFNb may induce the production of CXCL10 by peripheral mononuclear cells. [33] Blood collection from our MS patients was performed on the same day as IFNb administration, but the sample was taken before the drug was administered (as described in the Methods section). Therefore, the results of this study indicate that higher CXCL10 levels may persist for longer intervals (more than 36 hours, since the patients were on alternate-day or threetimes-a-week schedules).…”

Upregulation of the TLR3 Pathway by Kaposi's Sarcoma-Associated Herpesvirus during Primary Infection

“…IRF-1 is known to exert transcriptional control over CXCL10, TLR3, and IFN-␤1 (16,28), all of which were observed to be upregulated in KSHV-infected monocytes. It is possible that TLR3 activation stimulates IRF-1, which in turn activates both CXCL10 and IFN-␤1, leading to the promotion of the inflammatory response and a positive feedback loop.…”