Regulation of Vascular Cell Adhesion molecule-1 Expression by IL-4 and TNF-alpha in Cultured Endothelial Cells

J Clin Invest. 1995 Jan;95(1):264-71. doi: 10.1172/JCI117650.

Abstract

Interaction between vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells and alpha 4 integrins on leukocytes is thought to mediate the selective recruitment of eosinophils and lymphocytes that occurs in allergic diseases. IL-4 is associated with allergic conditions, and it has been shown to selectively increase expression of VCAM-1 on endothelial cells in vivo, suggesting that it could be responsible for VCAM-1 expression in allergic disease. Using a combination of immunofluorescence, flow cytometry, and Northern analysis, we compared the effect of TNF-alpha and IL-4 on VCAM-1 expression. TNF-alpha is also associated with allergic diseases, and it rapidly increases transcription of the VCAM-1 gene. The effect of IL-4 was relatively modest with prolonged kinetics: VCAM-1 was not detected until 72 h after treatment with IL-4. However, when TNF-alpha and IL-4 were combined, there was a synergistic increase in VCAM-1 expression and a dramatic prolongation of the appearance of VCAM-1 on the cell surface. This synergy results from a combination of transcriptional activation by TNF-alpha and the stabilization of resulting transcripts by IL-4. We propose that IL-4 allows subthreshold concentrations of TNF-alpha (concentrations that would not normally activate expression of adhesion molecules on the endothelium) to selectively increase VCAM-1 expression and to prolong its appearance on the surface of cells in allergic disease.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Adhesion
  • Cell Adhesion Molecules / biosynthesis*
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / isolation & purification
  • Cells, Cultured
  • Drug Synergism
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Regulation*
  • Half-Life
  • Humans
  • Hypersensitivity / etiology
  • Infant, Newborn
  • Interleukin-4 / pharmacology*
  • Kinetics
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Umbilical Veins
  • Vascular Cell Adhesion Molecule-1

Substances

  • Cell Adhesion Molecules
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Interleukin-4