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

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.