HETEROGENEOUS ACTIVATION THRESHOLDS TO CYTOKINES IN GENETICALLY DISTINCT ENDOTHELIAL-CELLS - EVIDENCE FOR DIVERSE TRANSCRIPTIONAL RESPONSES

It is well accepted that the induction of endothelial cell (EC) adhesi on molecules is a critical component in acute inflammatory responses a s well as allogeneic interactions in vascularized allografts and, poss ibly, atherogenesis. The ''inflammatory triad'' of interleukin 1 (IL-1 ), tumor necrosis factor, and lipopolysaccharide are potent stimulator s of the EC activation/adhesion molecules intercellular adhesion molec ule 1 (ICAM-1), endothelial-leukocyte adhesion molecule 1 (ELAM-1), an d vascular cell adhesion molecule 1 (VCAM-1). To address whether there exist differing thresholds to cytokine-mediated EC activation, we uti lized a panel of genetically distinct human umbilical vein EC lines, a ssessing their modulated EC surface expression and transcriptional res ponses to cytokines, with regard to the cell adhesion molecules (CAMs) ELAM-1, ICAM-1, and VCAM-1. With submaximal concentrations of cytokin e, EC ELAM-1 surface expression varied from negligible to marked. This phenotypic response was maintained over numerous passages in culture and was observed in ex vivo organ culture analyses with cytokine-treat ed umbilical vein sections. Relative patterns of ELAM-1, ICAM-1, and V CAM-1 induction were similar in response to multiple stimuli (IL-1, tu mor necrosis factor, and lipopolysaccharide, but not phorbol 12-myrist ate 13-acetate). Nuclear run-off experiments demonstrated that the ''h igh responder'' phenotype is a consequence of enhanced transcriptional activation of the CAM genes in response to IL-1 (1 unit/ml), whereas transcriptional responses in ''low responders'' are minimal. Despite t he known involvement of NF-kappa B in endothelial CAM transcription, g el shift assays failed to demonstrate a correlation between the levels of IL-1-mediated nuclear NF-kappa B expression and CAM induction in h igh and low responding lines. We postulate that varying EC activation thresholds to cytokines observed here, in vitro, may be a critical det erminant in the susceptibility to vasculopathic states.