We have definitely demonstrated that endothelial cells (EC) from human dermis (HDMEC) display skin-specific phenotypic and functional characteristics in vitro, and that these characteristics are reflective of in vivo biology of skin. Because of their importance in the pathophysiology of inflammatory skin disease, we have targeted for study the regulated expression of cytokine inducible cell adhesion molecules in HDMEC. Vascular cell adhesion molecule 1 (VCAM-1) is regulated in HDMEC in a cell-and cytokine-specific fashion and the in vitro patterns of expression are consistent with observations of in vivo expression in skin inflammation. The mechanisms that mediate cell-specific regulatory features are important targets for novel anti-inflammatory therapies, since interruption of these pathways may allow for targeting therapies specifically to skin. Indeed, we have demonstrated that specific inhibition of VCAM-1 in HDMEC can be mediated by all-trans retinoic acid (t-RA) in a cell-specific fashion. We have partially characterized the tissue-specific regulatory pathways that mediate the fine specificity of expression, response, and suppression. These HDMEC specific regulatory functions appear to localize to two distinct domains of the VCAM-1 promoter that regulate unique responses to IL-1 and t-RA, respectively. We hypothesize that the unique features of VCAM-1 expression in HDMEC are the result of HDMEC-specific transcriptional regulation of the VCAM-1 gene, and that cell-specific regulation is controlled by definable regions in the VCAM-1 promoter and by cell-specific expression or function of transcription factors that interact with these domains. Defining how expression is controlled in a tissue-specific manner will provide invaluable insights for developing skin therapeutics. We therefore propose to: 1) identify regulatory elements in the VCAM-1 gene promoter that confer unresponsiveness for VCAM-1 gene transcription in HDMEC in a cytokine- and cell-specific fashion. 2) identify key differences between HDMEC and other cell types in their repertoire of expression and function of NF-kappaB proteins and define the functional relevance these differences as they relate to VCAM-1 gene expression. Understanding the mechanisms that dictate organ-and cell-specific regulation of VCAM-1 in HDMEC is clearly an extremely important avenue of research. Most directly, these studies will yield information on how inflammation is induced and regulated in the skin, but understanding these regulatory pathways will also provide us with novel cell- and tissue-specific targets for drug therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR039632-13S1
Application #
6561739
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Moshell, Alan N
Project Start
1989-01-01
Project End
2003-06-30
Budget Start
2002-03-01
Budget End
2002-06-30
Support Year
13
Fiscal Year
2002
Total Cost
$27,205
Indirect Cost
Name
Emory University
Department
Dermatology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Gira, Amy K; Kowalczyk, Andrew P; Feng, Yue et al. (2009) Iron chelators and hypoxia mimetics inhibit IFNgamma-mediated Jak-STAT signaling. J Invest Dermatol 129:723-9
O'Reilly, Fiona M; Casper, Katherine A; Otto, Kristen B et al. (2003) Regulation of tissue factor in microvascular dermal endothelial cells. J Invest Dermatol 120:489-94
Gira, Amy K; Casper, Katherine A; Otto, Kristen B et al. (2003) Induction of interferon regulatory factor 1 expression in human dermal endothelial cells by interferon-gamma and tumor necrosis factor-alpha is transcriptionally regulated and requires iron. J Invest Dermatol 121:1191-6
Koo, Sang-Wahn; Casper, Katherine A; Otto, Kristen B et al. (2003) Iron chelators inhibit VCAM-1 expression in human dermal microvascular endothelial cells. J Invest Dermatol 120:871-9
Gille, J; Paxton, L L; Lawley, T J et al. (1997) Retinoic acid inhibits the regulated expression of vascular cell adhesion molecule-1 by cultured dermal microvascular endothelial cells. J Clin Invest 99:492-500
Gille, J; Swerlick, R A; Lawley, T J et al. (1996) Differential regulation of vascular cell adhesion molecule-1 gene transcription by tumor necrosis factor alpha and interleukin-1 alpha in dermal microvascular endothelial cells. Blood 87:211-7
Xu, Y; Swerlick, R A; Sepp, N et al. (1994) Characterization of expression and modulation of cell adhesion molecules on an immortalized human dermal microvascular endothelial cell line (HMEC-1). J Invest Dermatol 102:833-7
Swerlick, R A; Lee, K H; Wick, T M et al. (1992) Human dermal microvascular endothelial but not human umbilical vein endothelial cells express CD36 in vivo and in vitro. J Immunol 148:78-83