Exposing endothelial cells to tumor necrosis factor-α and peripheral blood mononuclear cells damage endothelial integrity via interleukin-1ß by degradation of vascular endothelial-cadherin

Surgery. 2014 Mar;155(3):545-53. doi: 10.1016/j.surg.2013.10.019. Epub 2013 Oct 15.


Background and purpose: We demonstrated previously that the administration of tumor necrosis factor alpha (TNF-α) for the treatment of solid tumors enhanced the response to chemotherapy by augmenting intratumoral drug accumulation. TNF-α changes the integrity of the endothelial cell monolayer in combination with interferon gamma (IFN-γ), which is further enhanced by the addition of peripheral blood mononuclear cells (PBMCs). The improved effect of PBMCs was mostly induced by the endogenous production of interleukin-1beta (IL-1ß) after TNF-α stimulation. In the current study, we demonstrate that exposing endothelial cells to TNF-α and PBMCs mediates the loss of vascular endothelial (VE)-cadherin, an important adherens junction protein for maintaining endothelial integrity, through endogenous IL-1ß. This loss increases permeability of the endothelial layer, thereby explaining the augmented passage of chemotherapeutics into the tumor.

Methods: Human umbilical vein endothelial cells were exposed to TNF-α, IFN-γ, PBMCs, or IL-1ß, and the effects on the endothelial integrity were assessed by morphological changes and permeability changes with the use of fluorescein isothiocyanate-labeled bovine serum albumin flux. The loss of VE-cadherin was assessed using immunofluorescence, western blotting, and polymerase chain reaction.

Results: Incubating endothelial cells with TNF-α, IFN-γ, and PBMCs increased cell elongation, gap formation, and subsequently the permeability of fluorescein isothiocyanate-labeled bovine serum albumin compared with control or TNF-α and IFN-γ-treated cells (P < .05). When PBMCs were replaced with IL-1ß, identical changes were observed. These changes in integrity were associated with a loss of VE-cadherin at the membrane.

Conclusion: We conclude that VE-cadherin is lost at the membrane when endothelial cells are exposed to TNF-α, IFN-γ, and PBMCs, which results in loss of integrity. IL-1ß can mimic the effects of PBMCs, indicating a dominant role of endogenously produced IL-1ß in this process.

Publication types

  • Evaluation Study

MeSH terms

  • Antigens, CD / metabolism*
  • Antineoplastic Agents / pharmacology*
  • Biomarkers / metabolism
  • Blotting, Western
  • Cadherins / metabolism*
  • Cell Membrane Permeability
  • Cells, Cultured
  • Fluorescent Antibody Technique
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / pathology
  • Humans
  • Interferon-gamma / pharmacology*
  • Interleukin-1beta / metabolism*
  • Leukocytes, Mononuclear / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Antigens, CD
  • Antineoplastic Agents
  • Biomarkers
  • Cadherins
  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha
  • cadherin 5
  • Interferon-gamma