Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1α.
Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1α.
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DOI：
10.1016/j.molcel.2011.07.037
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发表时间：
2011-10-21
期刊：
影响因子：
16
通讯作者：
Martin SJ
中科院分区：
文献类型：
--
作者：
Afonina IS;Tynan GA;Logue SE;Cullen SP;Bots M;Lüthi AU;Reeves EP;McElvaney NG;Medema JP;Lavelle EC;Martin SJ
颗粒酶B是一种细胞毒性淋巴细胞衍生的蛋白酶，通过直接蛋白水解和激活细胞死亡机制的成分，在促进病毒感染的靶细胞凋亡中发挥核心作用。然而，以前的研究也涉及颗粒酶A和B通过一种机制，促炎细胞因子的生产，仍然不确定。在这里，我们表明，IL-1α是颗粒酶B的底物，蛋白水解在体外和体内有效地增强了这种细胞因子的生物活性。与此一致，与全长IL-1α相比，颗粒酶B加工的IL-1α在体内表现出更有效的免疫佐剂活性。此外，还发现通过蛋白酶如钙蛋白酶和弹性蛋白酶在相同区域内对IL-1α进行蛋白水解可增强其生物学效力。因此，多种免疫相关蛋白酶（包括颗粒酶B）对IL-1α的加工可作为增强该细胞因子促炎特性的开关。
Granzyme B is a cytotoxic lymphocyte-derived protease that plays a central role in promoting apoptosis of virus-infected target cells, through direct proteolysis and activation of constituents of the cell death machinery. However, previous studies have also implicated granzymes A and B in the production of pro-inflammatory cytokines, via a mechanism that remains undefined. Here we show that IL-1α is a substrate for granzyme B and that proteolysis potently enhanced the biological activity of this cytokine in vitro as well as in vivo. Consistent with this, compared with full-length IL-1α, granzyme B-processed IL-1α exhibited more potent activity as an immunoadjuvant in vivo. Furthermore, proteolysis of IL-1α within the same region, by proteases such as calpain and elastase, was also found to enhance its biological potency. Thus, IL-1α processing by multiple immune-related proteases, including granzyme B, acts as a switch to enhance the pro-inflammatory properties of this cytokine.
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