Different PI 3-kinase inhibitors have distinct effects on endothelial permeability and leukocyte transmigration

TY - JOUR

T1 - Different PI 3-kinase inhibitors have distinct effects on endothelial permeability and leukocyte transmigration

AU - Cain, Rob

AU - Vanhaesebroeck, Bart

AU - Ridley, Anne J

PY - 2012/11

Y1 - 2012/11

N2 - 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.

AB - 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.

KW - Adenine

KW - Androstadienes

KW - Antigens, CD

KW - Cadherins

KW - Capillary Permeability

KW - Cell Membrane Permeability

KW - Cell Shape

KW - Class Ia Phosphatidylinositol 3-Kinase

KW - Dioxoles

KW - Endothelial Cells

KW - Focal Adhesion Kinase 2

KW - Furans

KW - Human Umbilical Vein Endothelial Cells

KW - Humans

KW - Leukocytes

KW - Phosphatidylinositol 3-Kinases

KW - Phosphorylation

KW - Protein Binding

KW - Protein Kinase Inhibitors

KW - Proto-Oncogene Proteins c-akt

KW - Pyridines

KW - Pyrimidines

KW - Quinazolines

KW - Signal Transduction

KW - TOR Serine-Threonine Kinases

KW - Thiazolidinediones

KW - Transendothelial and Transepithelial Migration

KW - Tumor Necrosis Factor-alpha

U2 - 10.1016/j.biocel.2012.07.009

DO - 10.1016/j.biocel.2012.07.009

M3 - Article

C2 - 22814170

SN - 1357-2725

VL - 44

SP - 1929

EP - 1936

JO - International Journal of Biochemistry and Cell Biology

JF - International Journal of Biochemistry and Cell Biology

IS - 11

ER -