Interleukin-33 drives a proinflammatory endothelial activation that selectively targets nonquiescent cells

Arterioscler Thromb Vasc Biol. 2013 Feb;33(2):e47-55. doi: 10.1161/ATVBAHA.112.253427. Epub 2012 Nov 15.


Objective: Interleukin (IL)-33 is a nuclear protein that is released from stressed or damaged cells to act as an alarmin. We investigated the effects of IL-33 on endothelial cells, using the prototype IL-1 family member, IL-1β, as a reference.

Methods and results: Human umbilical vein endothelial cells were stimulated with IL-33 or IL-1β, showing highly similar phosphorylation of signaling molecules, induction of adhesion molecules, and transcription profiles. However, intradermally injected IL-33 elicited significantly less proinflammatory endothelial activation when compared with IL-1β and led us to observe that quiescent endothelial cells (ppRb(low)p27(high)) were strikingly resistant to IL-33. Accordingly, the IL-33 receptor was preferentially expressed in nonquiescent cells of low-density cultures, corresponding to selective induction of adhesion molecules and chemokines. Multiparameter phosphoflow cytometry confirmed that signaling driven by IL-33 was stronger in nonquiescent cells. Manipulation of nuclear IL-33 expression by siRNA or adenoviral transduction revealed no functional link between nuclear, endogenous IL-33, and exogenous IL-33 responsiveness.

Conclusions: In contrast to other inflammatory cytokines, IL-33 selectively targets nonquiescent endothelial cells. By this novel concept, quiescent cells may remain nonresponsive to a proinflammatory stimulus that concomitantly triggers a powerful response in cells that have been released from contact inhibition.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Biopsy
  • Cell Proliferation*
  • Cells, Cultured
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Dermatitis / immunology*
  • Dermatitis / pathology
  • E-Selectin / metabolism
  • Endothelial Cells / immunology*
  • Endothelial Cells / pathology
  • Female
  • Flow Cytometry
  • Genetic Vectors
  • Human Umbilical Vein Endothelial Cells / immunology
  • Humans
  • Inflammation Mediators / metabolism*
  • Interleukin-1beta / metabolism
  • Interleukin-33
  • Interleukins / genetics
  • Interleukins / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Neovascularization, Physiologic
  • Phosphorylation
  • RNA Interference
  • Receptors, Interleukin / metabolism
  • Retinoblastoma Protein / metabolism
  • Signal Transduction
  • Skin / blood supply*
  • Transcription, Genetic
  • Transduction, Genetic
  • Transfection
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • CDKN1B protein, human
  • E-Selectin
  • IL33 protein, human
  • Il33 protein, mouse
  • Inflammation Mediators
  • Interleukin-1beta
  • Interleukin-33
  • Interleukins
  • NF-kappa B
  • Receptors, Interleukin
  • Retinoblastoma Protein
  • SELE protein, human
  • Cyclin-Dependent Kinase Inhibitor p27
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases