Hydrogen peroxide activation of endothelial cell-associated MMPS during VCAM-1-dependent leukocyte migration

Joan M. Cook-Mills*

*Corresponding author for this work

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Leukocyte migration from the blood into tissues is vital for immune surveillance and inflammation. Specificity for the site of leukocyte migration is determined by the combination and concentration of adhesion molecules, cytokines and chemokines in the microenvironment. Leukocytes bound at sites of extravasation migrate within minutes. We have focused on the function of the adhesion molecule VCAM-1 and have reported an active function for the endothelium during VCAM-1-dependent leukocyte migration. VCAM-1 activates endothelial cell NADPH oxidase followed by the generation of 1μM H 2O2. This stimulates endothelial cell-associated matrix metalloproteinase (MMP) activity in minutes, consistent with the time for lymphocyte migration. The endothelial cell NADPH oxidase and endothelial cell MMP activities are required for VCAM-1-dependent lymphocyte migration as determined by scavenging of ROS, by pharmacologic or antisense inhibition of NADPH oxidase and by pharmacologic inhibition of endothelial cell MMPs. Furthermore, antioxidants block VCAM-1 activation of MMPs. In vivo, administration of the antioxidant bilirubin blocks VCAM-1-dependent leukocyte migration into the lung in experimental asthma. In summary, endothelial cells are not simply a scaffold for leukocyte adhesion. Instead, endothelial cells have an active function during VCAM-1-dependent leukocyte transendothelial migration.

Original languageEnglish (US)
Pages (from-to)8-16
Number of pages9
JournalCellular and Molecular Biology
Volume52
Issue number4
DOIs
StatePublished - 2006

Keywords

  • Cell trafficking
  • Endothelial cells
  • Hydrogen peroxide
  • Matrix metalloproteinases
  • NADPH oxidase
  • Signal transduction
  • VCAM-1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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