Abstract
Endothelial cells are important reservoirs for human cytomegalovirus (HCMV) replication, dissemination and persistence. HCMV infection of endothelial cells has been associated with a proinflammatory response characterized by an increased expression of chemokines and adhesion molecules and modulation of angiogenesis. Many of the host proinflammatory genes augmented in HCMV-infected endothelial cells are regulated, at least in part, by the NF-kappaB pathway. HCMV is a potent activator of NF-kappaB through the IKK-IkappaB signaling axis. To explore whether inhibition of HCMV-induced NF-kappaB activation may interfere with the onset of virus-associated inflammatory response, we measured the effects of the specific IKK2 inhibitor AS602868 on the expression of a panel of proinflammatory genes in HUVEC cells infected with a clinical isolate. Treatment of infected HUVEC with AS602868 was shown to impair HCMV-induced NF-kappaB activity, IE gene expression, viral replication and to prevent HCMV-induced upregulation of ICAM-1, IL-8, RANTES, IP-10, I-TAC and COX-2 gene expression. Consistent with these results, HCMV-mediated upregulation of another NF-kappaB-dependent gene, the plasminogen inhibitor type-1, a regulatory factor of endothelial proliferation and angiogenesis, was abrogated by AS602868. These results suggest that inhibition of HCMV-induced IKK-NF-kappaB activation may be of interest to limit the virus-induced inflammatory response of infected endothelial cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Chemokine CCL5 / biosynthesis
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Chemokine CCL5 / genetics
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Chemokine CXCL10
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Chemokines, CXC / biosynthesis
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Chemokines, CXC / genetics
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Cyclooxygenase 2 / biosynthesis
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Cyclooxygenase 2 / genetics
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Cytomegalovirus / genetics
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Cytomegalovirus / metabolism
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Cytomegalovirus / physiology*
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Endothelial Cells / drug effects
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Endothelial Cells / immunology
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Endothelial Cells / metabolism
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Endothelial Cells / virology*
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Female
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Humans
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I-kappa B Kinase / antagonists & inhibitors*
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I-kappa B Kinase / metabolism
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Immediate-Early Proteins / biosynthesis
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Immediate-Early Proteins / genetics
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Inflammation / immunology
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Intercellular Adhesion Molecule-1 / biosynthesis
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Intercellular Adhesion Molecule-1 / genetics
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Interleukin-8 / biosynthesis
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Interleukin-8 / genetics
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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NF-kappa B / immunology
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NF-kappa B / metabolism*
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Oligopeptides / biosynthesis
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Oligopeptides / genetics
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Plasminogen Activator Inhibitor 1 / biosynthesis
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Plasminogen Activator Inhibitor 1 / genetics
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Pregnancy
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Pyrimidines / pharmacology*
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Up-Regulation / drug effects
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Viral Proteins / biosynthesis
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Viral Proteins / genetics
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Virus Replication / drug effects*
Substances
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AS602868
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CXCL10 protein, human
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Chemokine CCL5
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Chemokine CXCL10
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Chemokines, CXC
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IE1 protein, cytomegalovirus
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IE2 protein, Cytomegalovirus
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ITAC peptide
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Immediate-Early Proteins
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Interleukin-8
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Membrane Proteins
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NF-kappa B
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Oligopeptides
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Plasminogen Activator Inhibitor 1
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Pyrimidines
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Trans-Activators
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Viral Proteins
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Intercellular Adhesion Molecule-1
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Cyclooxygenase 2
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PTGS2 protein, human
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I-kappa B Kinase