RRC ID 54815
Author Naito H, Iba T, Wakabayashi T, Tai-Nagara I, Suehiro JI, Jia W, Eino D, Sakimoto S, Muramatsu F, Kidoya H, Sakurai H, Satoh T, Akira S, Kubota Y, Takakura N.
Title TAK1 Prevents Endothelial Apoptosis and Maintains Vascular Integrity.
Journal Dev. Cell
Abstract TNF-α is a pleiotropic cytokine that has the potential to induce apoptosis under inflammation. How endothelial cells (ECs) are spared from this fate in inflammatory environments where TNF-α is present is not known. Here, we show that TGF-β-activated kinase 1 (TAK1) ensures EC survival and maintains vascular integrity upon TNF-α stimulation. Endothelial-specific TAK1 knockout mice exhibit intestinal and liver hemorrhage due to EC apoptosis, leading to vascular destruction and rapid death. This EC apoptosis was induced by TNF-α from myeloid cells responding to intestinal microbiota. TNF-α secretion associated with inflammation also induced vascular defects in inflamed organs. Additionally, we determined that TAK1 deletion in tumor ECs resulted in blood vessel and hence tumor regression. Our results illuminate mechanisms ensuring survival of intestinal and liver ECs under physiological conditions and ECs of other organs under inflammatory conditions that could be exploited for anti-angiogenic therapy to treat cancer.
Volume 48(2)
Pages 151-166.e7
Published 2019-1-28
DOI 10.1016/j.devcel.2018.12.002
PII S1534-5807(18)31035-9
PMID 30639056
MeSH Animals Apoptosis / physiology Endothelial Cells / pathology* Hepatocytes / cytology* Inflammation / pathology* MAP Kinase Kinase Kinases / metabolism* Mice, Transgenic Signal Transduction / physiology
IF 9.616
Resource
Human and Animal Cells LLC(RCB0558) OP9(RCB1124)