Abstract
Endothelial cells play a central role in inflammatory responses, mediating leukocyte and solute traffic from blood vessels into the tissue, and are therefore key targets for anti-inflammatory therapies. Phosphoinositide 3-kinases (PI3Ks) are important signal transducers in inflammation and cancer, however there are 8 different PI3K catalytic isoforms, several of which have been shown to play distinct roles in cellular responses. Isoform-selective inhibitors have recently been described, but their effects on endothelial cell responses have not been compared. Here we compare the effects of the pan-PI3K inhibitor wortmannin with that of four more isoform-selective inhibitors, PI-103, TGX-221, AS604850 and IC87114, on endothelial cells stimulated with the pro-inflammatory cytokine TNFα. We find that PI-103 and wortmannin are most effective at reducing both endothelial permeability and leukocyte transendothelial migration (TEM), which correlates with a decrease in both the activity of the tyrosine kinase Pyk2 and its association with VE-cadherin. PI-103-related compounds are therefore likely to be good candidates for treating chronic inflammatory responses involving TNFα.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives
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Adenine / pharmacology
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Androstadienes / pharmacology
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Antigens, CD / metabolism
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Cadherins / metabolism
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Capillary Permeability / drug effects*
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Cell Membrane Permeability / drug effects*
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Cell Shape / drug effects
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Class Ia Phosphatidylinositol 3-Kinase / metabolism
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Dioxoles / pharmacology
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Endothelial Cells / cytology*
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Endothelial Cells / drug effects
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Endothelial Cells / enzymology
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Focal Adhesion Kinase 2 / metabolism
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Furans / pharmacology
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Leukocytes / cytology*
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Leukocytes / drug effects
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Leukocytes / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-akt / metabolism
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Pyridines / pharmacology
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Pyrimidines / pharmacology
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Quinazolines / pharmacology
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / metabolism
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Thiazolidinediones / pharmacology
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Transendothelial and Transepithelial Migration / drug effects*
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Tumor Necrosis Factor-alpha / pharmacology
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Wortmannin
Substances
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5-(2,2-difluorobenzo(1,3)dioxol-5-ylmethylene)thiazolidine-2,4-dione
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Androstadienes
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Antigens, CD
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Cadherins
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Dioxoles
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Furans
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IC 87114
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PI103
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Pyridines
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Pyrimidines
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Quinazolines
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Thiazolidinediones
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Tumor Necrosis Factor-alpha
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cadherin 5
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Class Ia Phosphatidylinositol 3-Kinase
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Focal Adhesion Kinase 2
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Adenine
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Wortmannin