Induction of plasminogen activator inhibitor-1 by urokinase in lung epithelial cells.
The plasminogen/plasmin system, urokinase-type plasminogen activator (uPA), its receptor (uPAR), and its inhibitor (PAI-1), influence extracellular proteolysis and cell migration in lung injury or neoplasia. In this study, we sought to determine whether tcuPA (two chain uPA) alters expression of its major inhibitor PAI-1 in lung epithelial cells. The expression of PAI-1 was evaluated at the protein and mRNA level by Western blot, immunoprecipitation, and Northern blot analyses. We found that tcuPA treatment enhanced PAI-1 protein and mRNA expression in Beas2B lung epithelial cells in a time- and concentration-dependent manner. The tcuPA-mediated induction of PAI-1 involves post-transcriptional control involving stabilization of PAI-1 mRNA. Inactivation of the catalytic activity of tcuPA had little effect on PAI-1 induction and the activity of the isolated amino-terminal fragment was comparable with full-length single- or two-chain uPA. In contrast, deletion of either the uPA receptor binding growth factor domain or kringle domain (kringle) from full-length single chain uPA markedly attenuated the induction of PAI-1. Induction of PAI-1 by exposure of lung epithelial cells to uPA is a newly recognized pathway by which PAI-1 could regulate local fibrinolysis and urokinase-dependent cellular responses in the setting of lung inflammation or neoplasia.
Shetty
Sreerama
S
Department of Specialty Care Services, University of Texas Health Center, Tyler, Texas 75708, USA.
Bdeir
Khalil
K
Cines
Douglas B
DB
Idell
Steven
S
D015152:Blotting, Northern; D015153:Blotting, Western; D002384:Catalysis; D020134:Catalytic Domain; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D010957:Plasmids / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D018076:DNA, Complementary; D008024:Ligands; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; D014568:Urokinase-Type Plasminogen Activator