Different PI 3-kinase inhibitors have distinct effects on endothelial permeability and leukocyte transmigration.
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.
Randall Division of Cell and Molecular Biophysics, King’s College London, New Hunt’s House, Guy’s Campus, London SE1 1UL, UK.
Robert J
RJ
Cain
Bart
B
Vanhaesebroeck
Anne J
AJ
Ridley
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D005663:Furans / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000077191:Wortmannin; D000099152:Cadherin 5
D000225:Adenine; D000730:Androstadienes; D015703:Antigens, CD; D015820:Cadherins; D058543:Class Ia Phosphatidylinositol 3-Kinase; D004149:Dioxoles; D051418:Focal Adhesion Kinase 2; D005663:Furans; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; D058570:TOR Serine-Threonine Kinases; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin; D000099152:Cadherin 5; C505145:5-(2,2-difluorobenzo(1,3)dioxol-5-ylmethylene)thiazolidine-2,4-dione; C477872:IC 87114; C522973:PI103