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.
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