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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

DOI

10.1016/j.ajpath.2012.06.003

Type

Journal article

Journal

The American journal of pathology

Publication Date

09/2012

Volume

181

Pages

1099 - 1111

Addresses

Laboratory for Immunohistochemistry and Immunopathology, Department of Pathology, Oslo University Hospital, Norway.

Keywords

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