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J Virol. 2005 Dec;79(24):15027-37.

Kaposi's sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways.

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Tumor Virology Program, Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.


Kaposi's sarcoma is an angioproliferative disseminated tumor of endothelial cells linked to infection with Kaposi's sarcoma-associated herpesvirus (KSHV). AP-1 transcription factors are involved in diverse biological processes, including infection and replication of viruses, cell growth, oncogenesis, angiogenesis, and invasion of cancer cells. Here we show that KSHV activates AP-1 during primary infection. The activation of AP-1 at the early stage of KSHV infection is mainly mediated by virus entry events. Concurrently, KSHV infection strongly activates MEK, JNK, and to a lesser extent, p38 mitogen-activated protein kinase (MAPK) pathways. Specific inhibitors or dominant negative constructs of MEK and JNK completely abolish AP-1 activation by KSHV, while those of p38 reduce it by half. Furthermore, individual MAPK pathways differentially regulate KSHV activation of AP-1 components. KSHV activation of AP-1 leads to the transcriptional induction of interleukin 6 (IL-6), which is inhibited by inhibitors or dominant negative constructs of MAPK pathways. Together, these results demonstrate that KSHV induces AP-1 and IL-6 during primary infection by modulating multiple MAPK pathways. Because of the diverse roles of IL-6, AP-1, and MAPK pathways in viral infection and tumor induction and promotion, these results have important implications in the pathogenesis of KSHV-induced malignancies.

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