The Alarmin IL-33 Is a Notch Target in Quiescent Endothelial Cells
| Autor: | Johanna Hol, Irina A. Udalova, Miriam Weiss, Kim S. Midwood, Monika Kasprzycka, Guttorm Haraldsen, Eirik Sundlisæter, Reidunn J Edelmann, Axel M. Küchler, Jon Sponheim |
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| Rok vydání: | 2012 |
| Předmět: |
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 |
| Zdroj: | The American Journal of Pathology. 181:1099-1111 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2012.06.003 |
| Popis: | 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 . |
| Databáze: | OpenAIRE |
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