We hypothesize that because of infections and immune dysregulation experienced by certain HIV-infected patients, Kaposi's sarcoma (KS) cells and their precursors are exposed to high levels of cytokines and to components of the infectious agents, such as double stranded RNA and lipopolysaccharide. We hypothesize that these agents activate NF-kappa- B-like transcription factors, and that this activation contributes to the induced expression of cellular adhesion molecules (CAMs) on KS cells and their precursors, thereby enhancing adhesion of specific types of leukocytes. These same agents also induce IL-6 expression by KS cells, suggesting that IL-6 expressed by the KS cells might contribute to activation of the adherent leukocytes. We hypothesize that these leukocytes provide factors, including the Tat protein of HIV and additional IL-6 and Oncostatin M, agents that are mediators in the development of KS. Although KS cells in culture maintain a phenotype that is distinct from other cell types that could be considered candidate precursors, neither CAM expression nor IL-6 expression is constitutive in KS cells, suggesting that host factors are responsible for the high levels of expression that occur in KS lesions. Because NF-kappa-B consensus sites exists in the regulatory regions of the CAMs, IL-6 and HIV, the shared molecule event of activation of NF-kappa-B could be necessary for many of the changes that lead to the development and progression of KS, and as such could serve as a target of clinical intervention. We have identified several mechanisms to interfere with NF-kappa-B-driven gene expression by these agents. These experiments are designed to enhance our understanding of the regulation of CAM and IL-6 expression in KS and the functional consequences of their induction by different agents. In addition, we will explore the consequences of targeting NF-gamma-B-like proteins as a shared transcription factor involved in the expression of these genes as a possible therapeutic strategy for the treatment of KS.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA060345-02
Application #
2101056
Study Section
AIDS and Related Research Study Section 5 (ARRE)
Project Start
1994-07-01
Project End
1997-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Harcourt, J L; Offermann, M K (2000) Interferon-alpha synergistically enhances induction of interleukin-6 by double stranded RNA in HeLa cells. Eur J Biochem 267:2768-77
Offermann, M K (1999) Consideration of host-viral interactions in the pathogenesis of Kaposi's sarcoma. J Acquir Immune Defic Syndr 21 Suppl 1:S58-65
Harcourt, B H; Sanchez, A; Offermann, M K (1999) Ebola virus selectively inhibits responses to interferons, but not to interleukin-1beta, in endothelial cells. J Virol 73:3491-6
Harcourt, B H; Rota, P A; Hummel, K B et al. (1999) Induction of intercellular adhesion molecule 1 gene expression by measles virus in human umbilical vein endothelial cells. J Med Virol 57:9-16
Kelly, G D; Morris, C B; Offermann, M K (1999) Lack of responsiveness of a nuclear factor-kappaB-regulated promoter to transactivation by human immunodeficiency virus 1 Tat in HeLa cells. Virology 263:128-38
Kelly, G D; Ensoli, B; Gunthel, C J et al. (1998) Purified Tat induces inflammatory response genes in Kaposi's sarcoma cells. AIDS 12:1753-61
Zimring, J C; Goodbourn, S; Offermann, M K (1998) Human herpesvirus 8 encodes an interferon regulatory factor (IRF) homolog that represses IRF-1-mediated transcription. J Virol 72:701-7
Offermann, M K; Lin, J C; Mar, E C et al. (1996) Antioxidant-sensitive regulation of inflammatory-response genes in Kaposi's sarcoma cells. J Acquir Immune Defic Syndr Hum Retrovirol 13:1-11
Offermann, M K (1996) HHV-8: a new herpesvirus associated with Kaposi's sarcoma. Trends Microbiol 4:383-6
Offermann, M K; Zimring, J; Mellits, K H et al. (1995) Activation of the double-stranded-RNA-activated protein kinase and induction of vascular cell adhesion molecule-1 by poly (I).poly (C) in endothelial cells. Eur J Biochem 232:28-36