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 language | English (US) |
|---|---|
| Pages (from-to) | 175-184 |
| Number of pages | 10 |
| Journal | Antiviral Research |
| Volume | 73 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2007 |
| Externally published | Yes |
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Keywords
- Endothelial cells
- Gene expression
- HCMV
- IKK2
- Inflammatory response
- NF-κB
ASJC Scopus subject areas
- Virology
- Pharmacology
Cite this
Targeting the NF-κB pathway through pharmacological inhibition of IKK2 prevents human cytomegalovirus replication and virus-induced inflammatory response in infected endothelial cells. / Caposio, Patrizia; Musso, Tiziana; Luganini, Anna; Inoue, Hiroyasu; Gariglio, Marisa; Landolfo, Santo; Gribaudo, Giorgio.
In: Antiviral Research, Vol. 73, No. 3, 03.2007, p. 175-184.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Targeting the NF-κB pathway through pharmacological inhibition of IKK2 prevents human cytomegalovirus replication and virus-induced inflammatory response in infected endothelial cells
AU - Caposio, Patrizia
AU - Musso, Tiziana
AU - Luganini, Anna
AU - Inoue, Hiroyasu
AU - Gariglio, Marisa
AU - Landolfo, Santo
AU - Gribaudo, Giorgio
PY - 2007/3
Y1 - 2007/3
N2 - 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.
AB - 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.
KW - Endothelial cells
KW - Gene expression
KW - HCMV
KW - IKK2
KW - Inflammatory response
KW - NF-κB
UR - http://www.scopus.com/inward/record.url?scp=33847027710&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33847027710&partnerID=8YFLogxK
U2 - 10.1016/j.antiviral.2006.10.001
DO - 10.1016/j.antiviral.2006.10.001
M3 - Article
C2 - 17070604
AN - SCOPUS:33847027710
VL - 73
SP - 175
EP - 184
JO - Antiviral Research
JF - Antiviral Research
SN - 0166-3542
IS - 3
ER -