Inhibition of Endothelial NOTCH1 Signaling Attenuates Inflammation by Reducing Cytokine-Mediated Histone Acetylation at Inflammatory Enhancers

OBJECTIVE—Endothelial upregulation of adhesion molecules serves to recruit leukocytes to inflammatory sites and appears to be promoted by NOTCH1; however, current models based on interactions between active NOTCH1 and NF-κB components cannot explain the transcriptional selectivity exerted by NOTCH1...

Full description

Saved in:

Bibliographic Details
Published in:	Arteriosclerosis, thrombosis, and vascular biology thrombosis, and vascular biology, 2018-04, Vol.38 (4), p.854-869
Main Authors:	Poulsen, Lars la Cour, Edelmann, Reidunn Jetne, Krüger, Stig, Diéguez-Hurtado, Rodrigo, Shah, Akshay, Stav-Noraas, Tor Espen, Renzi, Anastasia, Szymanska, Monika, Wang, Junbai, Ehling, Manuel, Benedito, Rui, Kasprzycka, Monika, Bækkevold, Espen, Sundnes, Olav, Midwood, Kim S, Scott, Helge, Collas, Philippe, Siebel, Christian W, Adams, Ralf H, Haraldsen, Guttorm, Sundlisæter, Eirik, Hol, Johanna
Format:	Article
Language:	eng ; nor
Subjects:	Acetylation Animals Appendicitis - metabolism Appendicitis - pathology Cells, Cultured Dermatitis, Contact - genetics Dermatitis, Contact - metabolism Dermatitis, Contact - pathology Dipeptides - pharmacology Disease Models, Animal Endothelial Cells - drug effects Endothelial Cells - metabolism Endothelial Cells - pathology Female Gene Expression Regulation - drug effects Histones - metabolism Human Umbilical Vein Endothelial Cells - drug effects Human Umbilical Vein Endothelial Cells - metabolism Human Umbilical Vein Endothelial Cells - pathology Humans Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism Inflammation - genetics Inflammation - metabolism Inflammation - pathology Inflammation - prevention & control Interleukin-1beta - pharmacology Male Mice, Inbred C57BL Mice, Transgenic Phenotype Receptor, Notch1 - antagonists & inhibitors Receptor, Notch1 - genetics Receptor, Notch1 - metabolism Signal Transduction - drug effects Transcription Factor RelA - genetics Transcription Factor RelA - metabolism
Online Access:	Request full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	OBJECTIVE—Endothelial upregulation of adhesion molecules serves to recruit leukocytes to inflammatory sites and appears to be promoted by NOTCH1; however, current models based on interactions between active NOTCH1 and NF-κB components cannot explain the transcriptional selectivity exerted by NOTCH1 in this context. APPROACH AND RESULTS—Observing that Cre/Lox-induced conditional mutations of endothelial Notch modulated inflammation in murine contact hypersensitivity, we found that IL (interleukin)-1β stimulation induced rapid recruitment of RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A) to genomic sites occupied by NOTCH1-RBPJ (recombination signal-binding protein for immunoglobulin kappa J region) and that NOTCH1 knockdown reduced histone H3K27 acetylation at a subset of NF-κB–directed inflammatory enhancers. CONCLUSIONS—Our findings reveal that NOTCH1 signaling supports the expression of a subset of inflammatory genes at the enhancer level and demonstrate how key signaling pathways converge on chromatin to coordinate the transition to an infla mmatory endothelial phenotype.
ISSN:	1079-5642 1524-4636