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Extracellular granzyme K mediates endothelial activation through the cleavage of protease‐activated receptor‐1
Author(s) -
Sharma Mehul,
Merkulova Yulia,
Raithatha Sheetal,
Parkinson Leigh G.,
Shen Yue,
Cooper Dawn,
Granville David J.
Publication year - 2016
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13699
Subject(s) - microbiology and biotechnology , granzyme , proinflammatory cytokine , biology , extracellular , granzyme b , cell adhesion molecule , proteases , granzyme a , intercellular adhesion molecule 1 , cancer research , inflammation , cytotoxic t cell , immunology , biochemistry , in vitro , perforin , enzyme
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.