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Journal of Virology, December 2005, p. 15027-15037, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15027-15037.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Induction of AP-1 and Interleukin 6 during Primary Infection Mediated by Multiple Mitogen-Activated Protein Kinase Pathways

Jianping Xie,^1,2, Hongyi Pan,^1,2, Seungmin Yoo,^1,2 and Shou-Jiang Gao^{1,2,3,4,5,6,7*}

Tumor Virology Program, Children's Cancer Research Institute,¹ Departments of Pediatrics,² Microbiology and Immunology,³ Medicine,⁴ Molecular Medicine,⁵ San Antonio Cancer Institute, The University of Texas Health Science Center, San Antonio, Texas,⁶ Tumor Virology Group, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China⁷

Received 20 June 2005/ Accepted 21 September 2005

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.

J.X. and H.P. contributed equally to this study.

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