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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.

Author information

1
Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
2
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
3
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.

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

PMID:
26936634
DOI:
10.1111/febs.13699
[Indexed for MEDLINE]
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