Submitted October 27, 2008
Accepted March 20, 2009
Induction of CCL20 production by Kaposi's sarcoma-associated herpesvirus: role of viral FLICE inhibitory protein K13-induced NF-
B activation
Vasu Punj, Hittu Matta, Sandra Schamus, Tianbing Yang, Yuan Chang, and Preet M. Chaudhary*
Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States
Spang Translational Research Core Facility, University of Pittsburgh Cancer Institute, Pittbsburgh, PA, United States
Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States
* Corresponding author; email: chaudharypm{at}upmc.edu.
Kaposi's sarcoma-associated herpesvirus (KSHV), also known as Human Herpesvirus 8 or HHV8, is the etiological agent of Kaposi's sarcoma, an angioproliferative lesion characterized by dramatic angiogenesis and inflammatory infiltration. In this study, we report that expression of chemokine CCL20, a potent chemoattractant of dendritic cells and lymphocytes, is strongly induced in cultured cells either by KSHV infection or upon ectopic expression of viral FLICE inhibitory protein (vFLIP) K13. This induction is caused by transcriptional activation of CCL20 gene, which is mediated by binding of the p65, p50 and c-Rel subunits of the transcription factor NF-
B to an atypical NF-B binding site present in the CCL20 gene promoter. The CCL20 gene-induction is defective in K13 mutants that lack NF-B activity, and can be blocked by specific genetic and pharmacological inhibitors of the NF-B pathway. CCR6, the specific receptor for CCL20, is also induced in cultured cells either by KSHV infection or upon K13 expression. Finally, expression of CCL20 and CCR6 is increased in clinical samples of KS. These results suggest that KSHV and K13-mediated induction of CCL20 and CCR6 may contribute to the recruitment of dendritic cells and lymphocytes into the KS lesions, and to tumor growth and metastases.
