Endothelial cell (EC) surface proteins contribute to several biological processes, including the recruitment of leukocytes in local inflammation. EC express adhesion molecules that serve to bind leukocytes, a key step in leukocyte extravasation. The expression of several these EC surface molecules is regulated. TNF or IL-1, inflammatory cytokines, induce the EC synthesis and expression of ELAM-1, VCAM-1 and ICAM-1. This expression may be further modulated by other cytokines, such as IFN-gamma or IL-4, by more classical inflammatory/vasoactive mediators such as histamine,by injurious stimuli such as complement membrane attack complex and by the local differentiation of the EC, determined by surrounding cells and matrix molecules. In this proposal, we will examine the regulation of adhesion molecule synthesis from transcriptional control to surface expression as well as of the regulation clearance of these molecules from the cell surface. We will identify factors that modulate the basic cytokine responses, exploring the bases of the anatomic heterogeneity of the EC response to cytokines. We will also explore the cytoplasmic signalling systems utilized by cytokines that activate transcription and identify the regulatory DNA sequences in the genes that render them cytokine responsive. These experiments will use cell and organ culture and will employ molecular, immunochemical and traditional biochemical approaches. The information generated by this proposal may open new therapeutic avenues to control inflammation by allowing pharmacological manipulation of EC adhesion molecule expression in vivo.
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