Extracellular granzyme K mediates endothelial activation through the cleavage of protease-activated receptor-1
Extracellular granzyme K mediates endothelial activation through the cleavage of protease-activated receptor-1
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DOI：
10.1111/febs.13699
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发表时间：
2016-05-01
期刊：
影响因子：
5.4
通讯作者：
Granville, David J.
中科院分区：
文献类型：
--
作者：
Sharma, Mehul;Merkulova, Yulia;Granville, David J.
颗粒酶是丝氨酸蛋白酶家族，其曾被认为仅作为细胞毒性淋巴细胞诱导的靶细胞死亡的介体起作用。然而，已经提出了颗粒酶，包括颗粒酶K（GzK）的非凋亡作用。由于最近的研究已经观察到临床脓毒症患者血浆中GzK水平升高，我们假设细胞外GzK诱导内皮细胞的促炎反应。在本研究中，细胞外GzK蛋白水解激活蛋白酶激活受体-1，导致内皮细胞中白细胞介素6和单核细胞趋化蛋白1的产生增加。还观察到随着THP-1细胞粘附能力的增加，细胞间粘附分子1沿着的表达增强。下游通路的表征涉及细胞间粘附分子1表达的促分裂原活化蛋白激酶p38通路，以及细胞因子产生中的p38和细胞外信号调节蛋白激酶1和2通路。GzK还增加肿瘤坏死因子α诱导的炎性粘附分子表达。此外，GzK的生理抑制剂，间-α-抑制蛋白，在体外显着抑制GzK活性。总之，细胞外GzK促进内皮细胞中的促炎反应。
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 alpha-induced inflammatory adhesion molecule expression. Furthermore, the physiological inhibitor of GzK, inter-alpha-inhibitor protein, significantly inhibited GzK activity in vitro. In summary, extracellular GzK promotes a proinflammatory response in endothelial cells.