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Heterogeneous activation thresholds to cytokines in genetically distinct endothelial cells: evidence for diverse transcriptional responses.

Abstract：

:It is well accepted that the induction of endothelial cell (EC) adhesion molecules is a critical component in acute inflammatory responses as well as allogeneic interactions in vascularized allografts and, possibly, atherogenesis. The "inflammatory triad" of interleukin 1 (IL-1), tumor necrosis factor, and lipopolysaccharide are potent stimulators of the EC activation/adhesion molecules intercellular adhesion molecule 1 (ICAM-1), endothelial-leukocyte adhesion molecule 1 (ELAM-1), and vascular cell adhesion molecule 1 (VCAM-1). To address whether there exist differing thresholds to cytokine-mediated EC activation, we utilized a panel of genetically distinct human umbilical vein EC lines, assessing their modulated EC surface expression and transcriptional responses to cytokines, with regard to the cell adhesion molecules (CAMs) ELAM-1, ICAM-1, and VCAM-1. With submaximal concentrations of cytokine, 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-treated umbilical vein sections. Relative patterns of ELAM-1, ICAM-1, and VCAM-1 induction were similar in response to multiple stimuli (IL-1, tumor necrosis factor, and lipopolysaccharide, but not phorbol 12-myristate 13-acetate). Nuclear run-off experiments demonstrated that the "high 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 the known involvement of NF-kappa B in endothelial CAM transcription, gel shift assays failed to demonstrate a correlation between the levels of IL-1-mediated nuclear NF-kappa B expression and CAM induction in high and low responding lines. We postulate that varying EC activation thresholds to cytokines observed here, in vitro, may be a critical determinant in the susceptibility to vasculopathic states.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Bender JR,Sadeghi MM,Watson C,Pfau S,Pardi R

doi

10.1073/pnas.91.9.3994

subject

Has Abstract

pub_date

1994-04-26 00:00:00

pages

3994-8

issue

eissn

0027-8424

issn

1091-6490

journal_volume

pub_type

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Heterogeneous activation thresholds to cytokines in genetically distinct endothelial cells: evidence for diverse transcriptional responses.