Targeting the NF-kappaB pathway through pharmacological inhibition of IKK2 prevents human cytomegalovirus replication and virus-induced inflammatory response in infected endothelial cells.
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.
Caposio
Patrizia
P
Department of Public Health and Microbiology, University of Torino, Via Santena, 9, 10126 Torino, Italy.
Musso
Tiziana
T
Luganini
Anna
A
Inoue
Hiroyasu
H
Gariglio
Marisa
M
Landolfo
Santo
S
Gribaudo
Giorgio
G
D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D007249:Inflammation / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D009842:Oligopeptides / Q000096:biosynthesis / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D011247:Pregnancy; D011743:Pyrimidines / Q000494:pharmacology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
C519899:AS602868; C114753:CXCL10 protein, human; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C088645:IE1 protein, cytomegalovirus; C069186:IE2 protein, Cytomegalovirus; C519300:ITAC peptide; D017874:Immediate-Early Proteins; D016209:Interleukin-8; D008565:Membrane Proteins; D016328:NF-kappa B; D009842:Oligopeptides; D017395:Plasminogen Activator Inhibitor 1; D011743:Pyrimidines; D015534:Trans-Activators; D014764:Viral Proteins; D018799:Intercellular Adhesion Molecule-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051550:I-kappa B Kinase