TRANSCRIPTIONAL CONTROL OF LEUKOCYTE ADHESION MOLECULES

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The adhesion of blood leukocytes to the vascular endothelium is an essential step in a variety of pathophysiological process. During the past project period, two inducible adhesion molecules were identified and characterized in detail in this Program Project. Both endothelial- leukocyte adhesion molecule-I (ELAM-1 or E-selectin) and vascular cell adhesion molecule (VCAM-1) are expressed by cultured endothelium after exposure to the cytokines interleukin-1beta or tumor necrosis factor- alpha. ELAM-1 is selectively expressed on human vascular endothelium in microvessels at sites of inflammation. VCAM-1 is a mononuclear-selective leukocyte adhesion molecule expressed by endothelial cells at sites of immune and non-immune inflammatory responses and atherosclerosis, as well as by dendritic cells. Detailed understanding of the regulation of expression of these cytokine-induced molecules may provide important insights into the control of inflammatory/immune processes. Specific Aim 1: Determine the role of NF-kB family members in the cytokine-induced activation and repression of ELAM-1 gene expression. Specific Aim 2: Characterize the endothelial inhibitors of NF-kB capable of regulating the cytokine-induced expression of the ELAM-1 gene. Specific Aim 3: To assemble several human ELAM-1 minigenes, insert these constructs into the germ line of mice and explore the pattern of transgene expression in several vascular beds in models of endothelial activation.