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

Jeffrey R. Bender, Mehran M. Sadeghi, Cornelius Watson, Steven Pfau, Ruggero Pardi

Research output: Contribution to journalArticlepeer-review

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-κB in endothelial CAM transcription, gel shift assays failed to demonstrate a correlation between the levels of IL-1-mediated nuclear NF-κB 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.

Original languageEnglish
Pages (from-to)3994-3998
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number9
Publication statusPublished - Apr 26 1994

Keywords

  • adhesion molecules
  • endothelium
  • heterogeneity
  • transcription

ASJC Scopus subject areas

  • General
  • Genetics

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