Characterization of Tie2 signalling during acute inflammation

作者：Tracy L. Smith · 发表于：TSpace (University of Toronto) · 年份：2018 · 研究领域：Wnt/β-catenin signaling in development and cancer、NF-κB Signaling Pathways、Cytokine Signaling Pathways and Interactions

The inflammatory response is essential for the eradication of lipopolysaccharide (LPS) presenting microbial invaders. However, resolution is also important to prevent detrimental vascular inflammation to the host. Endothelial cells play active roles in inflammation by detecting LPS using Toll-Like Receptor 4 (TLR4), leading to the activation of Nf-κB, but also participate in the resolution of inflammation, in part, through the actions of the receptor tyrosine kinase, Tie2. The process by which Tie2 can attenuate LPS-TLR4 driven inflammation is poorly understood. The work herein centers upon the characterization of Tie2 signalling during acute inflammation. The effects of Tie2 activation using the Tie2 agonist, Vasculotide (VT), was monitored in an animal model of endotoxin induced inflammation. Activation of Tie2 resulted in reductions in vascular permeability, levels of circulating inflammatory cytokines, and the number of leukocytes at the site of inflammation following LPS stimulation, confirming the anti-inflammatory effect of Tie2 signalling following LPS-TLR4 driven acute inflammation. To investigate the crosstalk between Tie2 and TLR4, Nf-κB activation was monitored in cells expressing Tie2 mutants harboring tyrosine (Y) to phenylalanine mutations in the carboxy-terminal tyrosine residues essential for downstream Tie2 signalling. Tie2 signalling reduced LPS induced Nf-κB activation in a Y1100 and Erk1/2 dependent manner. Tie2 signalling decreased the expression of the ...