Abstract
Granzymes are a family of serine proteases that were once thought to function exclusively as mediators of cytotoxic lymphocyte-induced target cell death. However, non-apoptotic roles for granzymes, including granzyme K (GzK), have been proposed. As recent studies have observed elevated levels of GzK in the plasma of patients diagnosed with clinical sepsis, we hypothesized that extracellular GzK induces a proinflammatory response in endothelial cells. In the present study, extracellular GzK proteolytically activated protease-activated receptor-1 leading to increased interleukin 6 and monocyte chemotactic protein 1 production in endothelial cells. Enhanced expression of intercellular adhesion molecule 1 along with an increased capacity for adherence of THP-1 cells was also observed. Characterization of downstream pathways implicated the mitogen-activated protein kinase p38 pathway for intercellular adhesion molecule 1 expression, and both the p38 and the extracellular signal-regulated protein kinases 1 and 2 pathways in cytokine production. GzK also increased tumour necrosis factor α-induced inflammatory adhesion molecule expression. Furthermore, the physiological inhibitor of GzK, inter-α-inhibitor protein, significantly inhibited GzK activity in vitro. In summary, extracellular GzK promotes a proinflammatory response in endothelial cells.
Keywords:
endothelial cells; granzyme K; inflammation; protease-activated receptors; serine proteases.
© 2016 Federation of European Biochemical Societies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alpha-Globulins / pharmacology
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Butadienes / pharmacology
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Cell Adhesion
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Cell Line
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Chemokine CCL2 / genetics
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Chemokine CCL2 / metabolism
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Gene Expression Regulation
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Granzymes / antagonists & inhibitors
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Granzymes / genetics
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Granzymes / metabolism
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Granzymes / 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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Imidazoles / pharmacology
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Monocytes / cytology
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Monocytes / drug effects*
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Monocytes / metabolism
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Nitriles / pharmacology
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Proteolysis / drug effects
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Pyridines / pharmacology
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Receptor, PAR-1 / antagonists & inhibitors
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Receptor, PAR-1 / genetics*
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Receptor, PAR-1 / metabolism
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Signal Transduction
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Alpha-Globulins
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Butadienes
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CCL2 protein, human
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Chemokine CCL2
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IL6 protein, human
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Imidazoles
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Interleukin-6
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Nitriles
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Pyridines
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Receptor, PAR-1
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U 0126
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inter-alpha-inhibitor
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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GZMK protein, human
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Granzymes
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4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole