CHEMOKINES, CYTOKINES, AND INTERLEUKINS 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

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 NFB, a nuclear factor playing a pivotal role in promoting inflammation and cell proliferation; however, little is known about NFB 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 NFB activity and function. HHV-8 rapidly and potently induced NFB activity in endothelial cells via stimulation of the I B 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 NFB–dependent proinflammatory proteins, including TNF, IL-8, and RANTES. Deletion of NFB–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 HHV8–induced MCP-1 may play an important role in promoting inflammation and pathogenic angiogenesis typical of HHV8–associated lesions. (Blood. 2007;109: 2718-2726)