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The molecular mechanisms that drive expression of the alarmin interleukin-33 (IL-33) in endothelial cells are unknown. Because nuclear IL-33 is a marker of endothelial cell quiescence (corroborated in this study by coexpression of cyclin-dependent kinase inhibitor p27(Kip1)), we hypothesized that Notch signaling might be involved in regulating IL-33 expression. Activation of Notch1 by immobilized Notch ligands was sufficient to induce nuclear IL-33 expression in cultured endothelial cells. Conversely, IL-33 expression was inhibited by the γ-secretase inhibitor DAPT or by inhibiting the function of Dll4, Jagged1, Notch1, or the canonical Notch transcription factor RBP-Jκ. Insensitivity to cycloheximide indicated that IL-33 was a direct target of Notch signaling, well in line with the identification of several conserved RBP-Jκ binding sites in the IL33 gene. The in vivo expression of Dll4 but not of Jagged1 was well correlated with expression of IL-33 in quiescent vessels, and subcutaneous injection of DAPT in healthy skin reduced IL-33 expression, indicating that Notch signaling was involved. On the other hand, loss of IL-33 during angiogenesis occurred despite sustained Dll4 and Notch1 expression, suggesting that other signals may override the IL-33-driving signal in this context. Taken together, our data demonstrate that endothelial nuclear IL-33 is induced by Notch and that Dll4 may be the dominant ligand responsible for this signaling in vivo.

Original publication




Journal article


Am j pathol

Publication Date





1099 - 1111


Amyloid Precursor Protein Secretases, Animals, Binding Sites, Biomarkers, Calcium-Binding Proteins, Cell Nucleus, Dipeptides, Down-Regulation, Endothelial Cells, Female, Genetic Loci, Genome, Human, Human Umbilical Vein Endothelial Cells, Humans, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Intercellular Signaling Peptides and Proteins, Interleukin-33, Interleukins, Jagged-1 Protein, Male, Membrane Proteins, Neovascularization, Physiologic, Protein Binding, Rats, Rats, Wistar, Receptor, Notch1, Serrate-Jagged Proteins, Signal Transduction, Wound Healing