Extracellular activities of human granzyme A. Monocyte activation by granzyme A versus alpha-thrombin.
Extracellular activities of human granzyme A. Monocyte activation by granzyme A versus alpha-thrombin.
复制标题
人颗粒酶 A 的细胞外活性。颗粒酶 A 与 α-凝血酶对单核细胞的激活。
DOI：
10.4049/jimmunol.156.7.2585
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发表时间：
1996
影响因子：
4.4
通讯作者：
G. Klimpel
中科院分区：
文献类型：
--
作者：
L. Sower;Christopher J. Froelich;N. Allegretto;P. M. Rose;W. Hanna;G. Klimpel
颗粒酶是位于细胞毒性T细胞和NK细胞颗粒中的丝氨酸蛋白酶，在诱导靶细胞凋亡中起着至关重要的作用。然而，由于细胞毒细胞结构性地分泌其合成的颗粒酶的一部分，这些蛋白酶可以独立于它们在裂解事件中的作用来调节细胞外功能。凝血酶是另一种丝氨酸蛋白酶，可以在许多不同类型的细胞中诱导细胞因子的产生。在这项研究中，我们验证了颗粒酶，如凝血酶，可以通过诱导不同细胞因子的产生来调节细胞免疫的假说。我们发现颗粒酶A(GA)能刺激人PBMC和纯化的单核细胞产生IL-6、IL-8和TNF-α。相比之下，单核细胞暴露于凝血酶时，IL-8的产生增加，而IL-6或肿瘤坏死因子-α的产生没有诱导。然而，暴露于GA或凝血酶的单核细胞具有增强的吞噬活性。GA和凝血酶的酶活性是诱导细胞因子产生和增强吞噬活性所必需的。GA和凝血酶诱导的不同细胞因子谱表明GA通过与凝血酶受体不同的受体激活单核细胞。GA不能诱导转入凝血酶受体的昆虫细胞中的钙动员，这一事实加强了这一结论。这些结果表明，具有酶活性的GA通过不涉及凝血酶受体激活的信号通路来调节重要的免疫调节功能。
Granzymes, serine proteases located in the granules of cytotoxic T cel ls and NK cells, are essential for induction of target cell apoptosis. However, since cytotoxic cells constitutively secrete a portion of their synthesized granzymes, these proteases could mediate extracellular functions independent of their role in the lytic event. Thrombin, another serine protease, can induce cytokine production in a number of different cell types. In this study, we test the hypothesis that granzymes, like thrombin, can regulate cell-mediated immunity by inducing the production of different cytokines. We show that granzyme A (GA) stimulates IL-6, IL-8, and TNF-alpha production by human PBMC and purified monocytes. In contrast, monocytes exposed to thrombin had enhanced IL-8 production with no induction of IL-6 or TNF-alpha production. However, monocytes exposed to either GA or thrombin had enhanced phagocytic activity. The enzymatic activity of GA and thrombin was required for the induction of cytokine production and for the enhancement of phagocytic activity. The induction of different cytokine profiles by GA vs thrombin suggested that GA activates monocytes via a receptor that was different from the thrombin receptor. This conclusion was strengthened by the fact that GA was incapable of inducing Ca2+ mobilization in insect cells transfected with the thrombin receptor. These results suggest that enzymatically active GA mediates important immunoregulatory functions through signaling pathways that does not involve thrombin receptor activation.