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JNCI Monographs 2000 2000(28):15-23;
© 2000 by Oxford University Press
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Journal of the National Cancer Institute Monographs, No. 28, 15-23, 2000
© 2000 Oxford University Press

Human Herpesvirus 8 K1-Associated Nuclear Factor-kappa B-Dependent Promoter Activity: Role in Kaposi's Sarcoma Inflammation?

Presented at the International Symposium on HIV, Leukemia, and Opportunistic Cancers.

Felipe Samaniego, Shibani Pati, Judith E. Karp, Om Prakash, Debashish Bose

Affiliations of authors: F. Samaniego, Departments of Lymphoma/Myeloma and Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston; S. Pati, D. Bose (Institute of Human Virology), J. E. Karp (The Greenebaum Cancer Center), University of Maryland, Baltimore; O. Prakash, Alton Ochsner Medical Foundation, New Orleans, LA.

Correspondence to: Felipe Samaniego, M.D., Department of Lymphoma/Myeloma and Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Box 429, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail fsamaniego{at}mdanderson.org).

Background: The growing number of human immunodeficiency virus type 1 (HIV-1) infections worldwide and the increasing use of immunosuppressive modalities for organ transplantation have contributed to an epidemic of Kaposi's sarcoma (KS), which has been etiologically linked to human herpesvirus 8 (HHV8) or KS-associated virus. Since the onset of the acquired immunodeficiency syndrome epidemic, inflammation has been recognized as an essential component of KS pathology. HHV8 bears a gene (K1) encoding a transmembrane protein with an immunoreceptor tyrosine-based activation motif. This motif is present in receptors that mediate inflammation. Purpose: To dissect the cellular effects of K1 function and the eventual role of K1 in KS, we developed a cell model for studying K1 expression. Methods: K1 was cloned from BC-3 lymphoma cells. To monitor transcriptional activation, K1 was coexpressed with plasmids containing luciferase under control of various promoters. K1 expression was monitored by indirect immunofluorescence and by combined immunoprecipitation/immunoblot analysis. Inflammatory cytokines were measured by enzyme-linked immunosorbent assay. Results: Cellular transfection of the K1 gene induced reporter expression under control of nuclear factor-kappa B (NF-{kappa}B), which controls the transcription of numerous proteins involved in inflammation. Treatment of cells with aspirin, an agent that targets this intracellular pathway and blocks cell inflammatory responses, blocked K1-induced NF-{kappa}B-dependent promoter activity. When a second KS cofactor, i.e., the HIV-1-transactivating gene tat, was coexpressed with K1, we observed an additive effect on NF-{kappa}B-dependent transcription. K1 transfection stimulated the secretion of cytokines interleukin (IL) 6, granulocyte–macrophage colony-stimulating factor, and IL-12. Cells treated with the conditioned media of K1 transfectants exhibited similar characteristics of K1 transfectants, indicating that a paracrine loop was being activated. Conclusion: Thus, K1 may activate cells in which it is expressed, as well as other cells in a paracrine manner. K1 cooperates in signaling with HIV-1 Tat, suggesting that both of the proteins from these viruses converge to reach an enhanced level of inflammation that may underlie progressive KS.


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