Protein tyrosine phosphorylation mediates TNF-induced endothelial-neutrophil adhesion in vitro

Susan A. Kelly, Pascal J. Goldschmidt-Clermont, Emily E. Milliken, Toshiyuki Arai, Elise H. Smith, Gregory B. Bulkley

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Proinflammatory cytokines initiate the vascular inflammatory response via the upregulation of adhesion molecules on the luminal endothelial surface. We investigated directly the role of protein tyrosine phosphorylation in the upregulation of the endothelial adhesion molecules, intercellular adhesion molecule 1 (ICAM-1) and E-selectin, and the consequent adhesion of neutrophils, after tumor necrosis factor (TNF)-α-stimulation of human aortic endothelial cells in vitro. Time- and dose-dependent TNF-α- stimulated ICAM-1 and E-selectin upregulation and neutrophil adhesion each were suppressed by tyrosine kinase inhibitors, including genistein (200 μM), but not genistin, its isoflavone analog without tyrosine kinase inhibitory activity. Tyrphostin AG 126, a synthetic selective tyrosine kinase inhibitor, also suppressed ICAM-1 and E-selectin upregulation and neutrophil adhesion, each in a dose-dependent manner, whereas tyrphostin AG 1288 had no effect. Tyrosine phosphorylation of two proteins (85 and 145 kDa in the cytoskeleton fraction) found minutes after TNF-α-stimulation was also inhibited by genistein. These findings suggest that, in endothelial cells, TNF-α upregulates ICAM-1 and E-selectin expression and consequent neutrophil adhesion via protein tyrosine phosphorylation.

Original languageEnglish (US)
Pages (from-to)H513-H519
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume274
Issue number2 43-2
DOIs
StatePublished - Feb 1998

Keywords

  • E- selectin
  • Genistein
  • Human
  • Intercellular adhesion molecule 1
  • Polymorphonuclear leukocyte
  • Tumor necrosis factor
  • Tyrphostin

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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