Submitted March 23, 2006
Accepted November 11, 2006
Human herpesvirus 8 acute infection of endothelial cells induces monocyte chemoattractant protein 1-dependent capillary-like structure formation: role of the IKK/NF-
B pathway
Elisabetta Caselli, Simona Fiorentini, Carla Amici, Dario Di Luca, Arnaldo Caruso, and M. Gabriella Santoro*
Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy
Department of Experimental and Applied Medicine, University of Brescia, Brescia, Italy
Department of Biology, University of Rome Tor Vergata, Rome, Italy
* Corresponding author; email: santoro{at}bio.uniroma2.it.
Human herpesvirus 8 (HHV-8) is considered the causative agent of Kaposi's sarcoma, a highly vascularized neoplasm characterized by spindle-shape cells of endothelial origin and inflammatory cell infiltration. HHV-8 cell-transforming ability has been associated with the activation of NF-
B, a nuclear factor playing a pivotal role in promoting inflammation and cell proliferation; however, little is known on NF-B activation during acute HHV-8 infection. In the present report, we utilized a recently established in vitro model of HHV-8 acute productive infection in endothelial cells to investigate the effect of HHV-8 on NF-B activity and function. HHV-8 was found to rapidly and potently induce NF-B activity in endothelial cells via stimulation of the IB kinase (IKK). Following IKK activation, HHV-8 selectively triggered the production of high levels of monocyte chemoattractant protein-1 (MCP-1), while it did not affect the expression of other NF-B-dependent proinflammatory proteins, including TNF
, interleukin-8 and RANTES. Deletion of NF-B-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.
