TAK1 Prevents Endothelial Apoptosis and Maintains Vascular Integrity.

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.

• Authors: Hisamichi Naito, Tomohiro Iba, Taku Wakabayashi, Ikue Tai-Nagara, Jun-Ichi Suehiro, Weizhen Jia, Daisuke Eino, Susumu Sakimoto, Fumitaka Muramatsu, Hiroyasu Kidoya, Hiroyuki Sakurai, Takashi Satoh, Shizuo Akira, Yoshiaki Kubota, Nobuyuki Takakura
• Journal: Developmental cell (Dev Cell) Vol. 48 Issue 2 Pg. 151-166.e7 (01 28 2019) ISSN: 1878-1551 [Electronic] United States
• PMID: 30639056 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Animals
• Apoptosis (physiology)
• Endothelial Cells (pathology)
• Hepatocytes (cytology)
• Inflammation (pathology)
• MAP Kinase Kinase Kinases (metabolism)
• Mice, Transgenic
• Signal Transduction (physiology)