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FEBS J. 2016 May;283(9):1734-47. doi: 10.1111/febs.13699. Epub 2016 Mar 22.

Extracellular granzyme K mediates endothelial activation through the cleavage of protease-activated receptor-1.

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Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.


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.


endothelial cells; granzyme K; inflammation; protease-activated receptors; serine proteases

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