1. The Alarmin IL-33 Is a Notch Target in Quiescent Endothelial Cells
- Author
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Johanna Hol, Irina A. Udalova, Miriam Weiss, Kim S. Midwood, Monika Kasprzycka, Guttorm Haraldsen, Eirik Sundlisæter, Reidunn J Edelmann, Axel M. Küchler, and Jon Sponheim
- Subjects
Male ,Angiogenesis ,Notch signaling pathway ,Down-Regulation ,Neovascularization, Physiologic ,Biology ,Pathology and Forensic Medicine ,Serrate-Jagged Proteins ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Rats, Wistar ,Receptor, Notch1 ,Transcription factor ,Adaptor Proteins, Signal Transducing ,Cell Nucleus ,Wound Healing ,Binding Sites ,Genome, Human ,Interleukins ,Calcium-Binding Proteins ,Endothelial Cells ,Membrane Proteins ,Dipeptides ,Interleukin-33 ,Rats ,Cell biology ,Interleukin 33 ,Endothelial stem cell ,Notch proteins ,Genetic Loci ,Immunoglobulin J Recombination Signal Sequence-Binding Protein ,cardiovascular system ,Intercellular Signaling Peptides and Proteins ,Jagged-1 Protein ,Female ,Amyloid Precursor Protein Secretases ,Biomarkers ,Protein Binding ,Signal Transduction - Abstract
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 . more...
- Published
- 2012
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