Human herpesvirus 8 acute infection of endothelial cells induces monocyte chemoattractant protein 1-dependent capillary-like structure formation: role of the IKK/NF-kappaB pathway.
Human herpesvirus 8 (HHV-8) is considered the causative agent of Kaposi sarcoma, a highly vascularized neoplasm characterized by spindle-shaped cells of endothelial origin and inflammatory cell infiltration. The cell transforming ability of HHV-8 has been associated with the activation of NF-kappaB, a nuclear factor playing a pivotal role in promoting inflammation and cell proliferation; however, little is known about NF-kappaB activation during acute HHV-8 infection. In the present study, we used a recently established in vitro model of HHV-8 acute productive infection in endothelial cells to investigate the effect of HHV-8 on NF-kappaB activity and function. HHV-8 rapidly and potently induced NF-kappaB activity in endothelial cells via stimulation of the IkappaB kinase (IKK). Following IKK activation, HHV-8 selectively triggered the production of high levels of monocyte chemoattractant protein 1 (MCP-1), whereas it did not affect the expression of other NF-kappaB-dependent proinflammatory proteins, including TNF-alpha, IL-8, and RANTES. Deletion of NF-kappaB-binding sites in the MCP-1 enhancer resulted in significant inhibition of HHV-8-induced transcription. Furthermore, MCP-1 production was accompanied by virus-induced capillary-like structure formation at early stages of infection. The results suggest that HHV-8-induced MCP-1 may play an important role in promoting inflammation and pathogenic angiogenesis typical of HHV-8-associated lesions.
Caselli
Elisabetta
E
Section of Microbiology, Department of Experimental and Diagnostic Medicine, University of Ferrara, Italy.
Fiorentini
Simona
S
Amici
Carla
C
Di Luca
Dario
D
Caruso
Arnaldo
A
Santoro
M Gabriella
MG
D002196:Capillaries / Q000473:pathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000502:physiology*; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology*; D015870:Gene Expression; D006566:Herpesviridae Infections / Q000235:genetics / Q000473:pathology / Q000821:virology; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D009389:Neovascularization, Pathologic; D012514:Sarcoma, Kaposi / Q000098:blood supply / Q000209:etiology / Q000235:genetics / Q000821:virology
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016328:NF-kappa B; D051550:I-kappa B Kinase