HUMAN INTERCELLULAR-ADHESION MOLECULE-1 GENE AND ITS EXPRESSION IN THE SKIN

Cell adhesion molecules are cell-surface proteins that allow specific cell-cell interactions among leukocytes, as well as between leukocytes and other cells. Recent studies have shown that the differential expression of selected cell-adhesion molecules plays a critical role in cutaneous inflammation, immunologic responses, and wound repair. Intercellular adhesion molecule-1 (ICAM-1) is a cell-adhesion molecule that is constitutively expressed on human dermal microvascular endothelial cells (HDMEC) and is inducible on human keratinocytes (HK). Its regulated expression is vital to the initiation and evolution of localized inflammatory processes in the skin. ICAM-1 serves as a specific ligand for lymphocyte function-associated antigen-1 (LFA-1), a cell-surface protein expressed on all leukocytes. The regulated expression of ICAM-1 allows leukocytes to bind to endothelial cells at sites of inflammation and, after exiting into the tissue, to interact with specific target cells, such as HK. Furthermore, specific cytokines are capable of differentially regulating ICAM-1 expression on HDMEC, HK, and other cells. The biologic relevance of ICAM-1 expression in cutaneous inflammation is further supported by functional studies demonstrating the critical role of ICAM-l/LFA-1 interactions in mediating the binding of peripheral blood leukocytes to HDMEC and to HK-cells known to be participants and targets in specific cutaneous immunologic responses. Thus, the delineation of precise molecular mechanisms that regulate the tissue-specific and cytokine-specific expression if ICAM-1 is important to both our understanding of the biology of localized inflammation and to the development of directed anti-inflammatory therapeutic strategies. Current evidence indicates that ICAM-1 expression is regulated at the level of gene transcription. Recently our laboratory has isolated and characterized a human genomic clone that contains the 5' regulatory region of the ICAM-1 gene. In the current studies, we further describe the genomic ICAM-1 clones isolated to date and demonstrate the presence of consensus regulatory elements located within the 5' flanking region of the ICAM-1 gene that are potentially involved in regulating ICAM-1 gene transcription.