Targeting the NF-κB pathway through pharmacological inhibition of IKK2 prevents human cytomegalovirus replication and virus-induced inflammatory response in infected endothelial cells

Patrizia Caposio, Tiziana Musso, Anna Luganini, Hiroyasu Inoue, Marisa Gariglio, Santo Landolfo, Giorgio Gribaudo

Research output: Contribution to journalArticle

36 Scopus citations

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-κB pathway. HCMV is a potent activator of NF-κB through the IKK-IκB signaling axis. To explore whether inhibition of HCMV-induced NF-κB 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-κB 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-κB-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-κB activation may be of interest to limit the virus-induced inflammatory response of infected endothelial cells.

Original languageEnglish (US)
Pages (from-to)175-184
Number of pages10
JournalAntiviral Research
Volume73
Issue number3
DOIs
StatePublished - Mar 1 2007

Keywords

  • Endothelial cells
  • Gene expression
  • HCMV
  • IKK2
  • Inflammatory response
  • NF-κB

ASJC Scopus subject areas

  • Pharmacology
  • Virology

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