Cell adhesion molecules are cell surface proteins that mediate cell-cell and cell-matrix interactions. These molecules play a critical role in the initiation, localization, and evolution of immunologic and inflammatory processes. Their expression and interaction with other cells and pathogens are important in wound healing, tumor metastasis, and many other pathologic and homeostatic events. Intercellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin gene superfamily, and its regulated expression has been implicated as playing a pivotal role in cutaneous inflammation and tissue repair. In the skin, ICAM-1 is constitutively expressed by human dermal microvascular endothelial cells (HDMEC) and serves as a specific ligand for LFA-1, a cell surface protein expressed on the surface of all white blood cells. The regulated expression of ICAM-1 allows leukocytes to bind to endothelial cells at sites of inflammation, and after egressing into the tissue, to bind to specific target cells, such as keratinocytes (HK). ICAM-1 expression is differentially regulated in cells of the skin. While HDMEC constitutively express ICAM-1, HK do not. Its expression can be rapidly induced in both HDMEC and HK by exposure to specific cytokines, yet cytokine-induced expression of ICAM-1 is differentially regulated as well. Thus there are both tissue-specific and cytokine-specific regulatory mechanisms involved in its expression, and data indicate that these events occur at the level of gene transcription. Because the regulated expression of this gene appears to be so vitally important to both physiologic and pathologic processes in the skin and other tissues, we have chosen to examine the regulation and function of the ICAM-1 gene as a model for differential regulation of immunologically important genes. Recently our laboratory became the first to isolate and characterize a human genomic clone containing the 5' transcriptional regulatory region of the ICAM-1 gene. With this critical genomic material in hand, we propose to delineate the molecular regulation of this gene by (1) identifying and characterizing functionally the basal transcriptional regulatory components contained within this gene; (2) identifying the specific sequences within the ICAM-1 transcriptional regulatory region that confer cytokine-specific transcriptional activation; (3) characterizing the specific trans-acting proteins expressed in either HK or HDMEC that specifically bind the identified tissue-specific and cytokine-responsive cis-elements of the ICAM-1 gene; and (4) determining the molecular mechanisms whereby selected modalities modulate ICAM-1 gene transcription in HK and HDMEC. Through elucidation of the molecular mechanisms by which the ICAM-1 gene is differentially regulated, these studies will provide important information concerning the role of adhesion molecule regulation in directing inflammatory processes. They also will provide insights into novel strategies for modulating and inhibiting adhesion molecule expression, and thus may result in new therapeutic approaches to immunologic and inflammatory disorders affecting the skin and other tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR041206-01
Application #
3161639
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1992-01-03
Project End
1995-12-31
Budget Start
1992-01-03
Budget End
1992-12-31
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Quinlan, K L; Song, I S; Naik, S M et al. (1999) VCAM-1 expression on human dermal microvascular endothelial cells is directly and specifically up-regulated by substance P. J Immunol 162:1656-61
Naik, S M; Cannon, G; Burbach, G J et al. (1999) Human keratinocytes constitutively express interleukin-18 and secrete biologically active interleukin-18 after treatment with pro-inflammatory mediators and dinitrochlorobenzene. J Invest Dermatol 113:766-72
Quinlan, K L; Naik, S M; Cannon, G et al. (1999) Substance P activates coincident NF-AT- and NF-kappa B-dependent adhesion molecule gene expression in microvascular endothelial cells through intracellular calcium mobilization. J Immunol 163:5656-65
Daneker, G W; Lund, S A; Caughman, S W et al. (1998) Culture and characterization of sinusoidal endothelial cells isolated from human liver. In Vitro Cell Dev Biol Anim 34:370-7
Quinlan, K L; Song, I S; Bunnett, N W et al. (1998) Neuropeptide regulation of human dermal microvascular endothelial cell ICAM-1 expression and function. Am J Physiol 275:C1580-90
Duff, J L; Quinlan, K L; Paxton, L L et al. (1997) Pervanadate mimics IFNgamma-mediated induction of ICAM-1 expression via activation of STAT proteins. J Invest Dermatol 108:295-301
Naik, S M; Shibagaki, N; Li, L J et al. (1997) Interferon gamma-dependent induction of human intercellular adhesion molecule-1 gene expression involves activation of a distinct STAT protein complex. J Biol Chem 272:1283-90
Gille, J; Swerlick, R A; Caughman, S W (1997) Transforming growth factor-alpha-induced transcriptional activation of the vascular permeability factor (VPF/VEGF) gene requires AP-2-dependent DNA binding and transactivation. EMBO J 16:750-9
Baeuml, H; Behrends, U; Peter, R U et al. (1997) Ionizing radiation induces, via generation of reactive oxygen intermediates, intercellular adhesion molecule-1 (ICAM-1) gene transcription and NF kappa B-like binding activity in the ICAM-1 transcriptional regulatory region. Free Radic Res 27:127-42
Paxton, L L; Li, L J; Secor, V et al. (1997) Flanking sequences for the human intercellular adhesion molecule-1 NF-kappaB response element are necessary for tumor necrosis factor alpha-induced gene expression. J Biol Chem 272:15928-35

Showing the most recent 10 out of 15 publications