کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6255613 | 1289248 | 2014 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Exposing endothelial cells to tumor necrosis factor-α and peripheral blood mononuclear cells damage endothelial integrity via interleukin-1à by degradation of vascular endothelial-cadherin Exposing endothelial cells to tumor necrosis factor-α and peripheral blood mononuclear cells damage endothelial integrity via interleukin-1à by degradation of vascular endothelial-cadherin](/preview/png/6255613.png)
Background and purposeWe 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-1Ã) 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-1Ã. This loss increases permeability of the endothelial layer, thereby explaining the augmented passage of chemotherapeutics into the tumor.MethodsHuman umbilical vein endothelial cells were exposed to TNF-α, IFN-γ, PBMCs, or IL-1Ã, 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.ResultsIncubating 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-γâtreated cells (P < .05). When PBMCs were replaced with IL-1Ã, identical changes were observed. These changes in integrity were associated with a loss of VE-cadherin at the membrane.ConclusionWe 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-1à can mimic the effects of PBMCs, indicating a dominant role of endogenously produced IL-1à in this process.
Journal: Surgery - Volume 155, Issue 3, March 2014, Pages 545-553