Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation

Am J Pathol. 2008 Oct;173(4):1229-42. doi: 10.2353/ajpath.2008.080014. Epub 2008 Sep 11.


Interleukin (IL)-33 is a novel member of the IL-1 family of cytokines that promotes Th2 responses in lymphocytes as well as the activation of both mast cells and eosinophils via the ST2 receptor. Additionally, IL-33 has been proposed to act as a chromatin-associated transcriptional regulator in both endothelial cells of high endothelial venules and chronically inflamed vessels. Here we show that nuclear IL-33 is expressed in blood vessels of healthy tissues but down-regulated at the earliest onset of angiogenesis during wound healing; in addition, it is almost undetectable in human tumor vessels. Accordingly, IL-33 is induced when cultured endothelial cells reach confluence and stop proliferating but is lost when these cells begin to migrate. However, IL-33 expression was not induced by inhibiting cell cycle progression in subconfluent cultures and was not prevented by antibody-mediated inhibition of VE-cadherin. Conversely, IL-33 knockdown did not induce detectable changes in either expression levels or the cellular distribution of either VE-cadherin or CD31. However, activation of endothelial cell cultures with either tumor necrosis factor-alpha or vascular endothelial growth factor and subcutaneous injection of these cytokines led to a down-regulation of vascular IL-33, a response consistent with both its rapid down-regulation in wound healing and loss in tumor endothelium. In conclusion, we speculate that the proposed transcriptional repressor function of IL-33 may be involved in the control of endothelial cell activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / drug effects
  • Blood Vessels / metabolism
  • Cell Count
  • Cell Movement / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Cytokines / pharmacology
  • Down-Regulation / drug effects
  • Endothelium / drug effects
  • Endothelium / metabolism*
  • Endothelium / pathology
  • Female
  • Health
  • Humans
  • Inflammation / metabolism*
  • Interleukin-33
  • Interleukins / metabolism*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neovascularization, Pathologic / metabolism*
  • Rats
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Endothelial Growth Factor A / pharmacology
  • Wound Healing / drug effects


  • Cytokines
  • IL33 protein, human
  • Interleukin-33
  • Interleukins
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A