Urokinase-type plasminogen activator potentiates lipopolysaccharide-induced neutrophil activation.
Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin. Although increased circulating levels of uPA are present in endotoxemia and sepsis, conditions in which activated neutrophils contribute to the development of acute organ dysfunction, the ability of uPA to participate directly in LPS-induced neutrophil activation has not been examined. In the present experiments, we show that uPA can enhance activation of neutrophils exposed to submaximal stimulatory doses of LPS. In particular, uPA increased LPS-induced activation of intracellular signaling pathways, including Akt and c-Jun N-terminal kinase, nuclear translocation of the transcriptional regulatory factor NF-kappa B, and expression of proinflammatory cytokines, including IL-1 beta, macrophage-inflammatory protein-2, and TNF-alpha. There was no effect of uPA on LPS-induced activation of p38 mitogen-activated protein kinase in neutrophils. Transgenic mice unable to produce uPA (uPA(-/-)) were protected from endotoxemia-induced lung injury, as determined by development of lung edema, pulmonary neutrophil accumulation, lung IL-1 beta, macrophage-inflammatory protein-2, and TNF-alpha cytokine levels. These results demonstrate that uPA can potentiate LPS-induced neutrophil responses and also suggest that such effects are sufficiently important in vivo to play a major contributory role in neutrophil-mediated inflammatory responses, such as the development of acute lung injury.
Abraham
Edward
E
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA. edward.abraham@uchsc.edu
Gyetko
Margaret R
MR
Kuhn
Katherine
K
Arcaroli
John
J
Strassheim
Derek
D
Park
Jong Sung
JS
Shetty
Sreerama
S
Idell
Steven
S
D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D000208:Acute Disease; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004357:Drug Synergism; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator