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
N1 - Funding Information:
We wish to thank Michel Dreano for providing the AS602868 and Giuseppe Gerna for the VR1814 HCMV strain. This work was supported by grants from Ministry of Education and University Research (MIUR) (PRIN and 60%) and from the Ricerca Scientifica Applicata and Ricerca Sanitaria Finalizzata (Region of Piedmont, Italy).
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
SN - 0166-3542
VL - 73
SP - 175
EP - 184
JO - Antiviral Research
JF - Antiviral Research
IS - 3
ER -