Are all granzymes cytotoxic in vivo?
Are all granzymes cytotoxic in vivo?
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DOI：
10.1515/hsz-2013-0238
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发表时间：
2014-02-01
影响因子：
3.7
通讯作者：
Bird, Phillip I.
中科院分区：
文献类型：
--
作者：
Joeckel, Lars T.;Bird, Phillip I.
颗粒酶是主要存在于细胞毒性淋巴细胞中的丝氨酸蛋白酶。该组中研究最多的成员是颗粒酶 B，它是一种强效细胞毒素，为所有颗粒酶都具有细胞毒性奠定了基础。在过去的五年里，这种范式引起了争议。一方面，有大量有时相互矛盾的出版物显示颗粒酶 A 和所谓的孤儿颗粒酶在体外主要具有不依赖 caspase 的细胞毒性作用。另一方面，越来越多的报道表明，除非使用非常高的（可能超生理的）浓度，否则颗粒酶无法在体外诱导细胞死亡。此外，用颗粒酶A或颗粒酶M敲除小鼠进行的实验表明，其细胞毒性淋巴细胞的离体杀伤能力几乎没有缺陷，但表明炎症反应受损。颗粒酶的非细胞毒性作用的这些发现挑战了教条，因此需要对颗粒酶在击败病原体中的作用进行替代或额外的解释。在这里，我们回顾了颗粒酶细胞毒性的证据，概述了它们的非细胞毒性功能，并为未来的研究提出了技术改进建议。
Granzymes are serine proteases mainly found in cytotoxic lymphocytes. The most-studied member of this group is granzyme B, which is a potent cytotoxin that has set the paradigm that all granzymes are cyototoxic. In the last 5 years, this paradigm has become controversial. On one hand, there is a plethora of sometimes contradictory publications showing mainly caspase-independent cytotoxic effects of granzyme A and the so-called orphan granzymes in vitro. On the other hand, there are increasing numbers of reports of granzymes failing to induce cell death in vitro unless very high (potentially supra-physiological) concentrations are used. Furthermore, experiments with granzyme A or granzyme M knock-out mice reveal little or no deficit in their cytotoxic lymphocytes' killing ability ex vivo, but indicate impairment in the inflammatory response. These findings of non-cytotoxic effects of granzymes challenge dogma, and thus require alternative or additional explanations to be developed of the role of granzymes in defeating pathogens. Here we review evidence for granzyme cytotoxicity, give an overview of their non-cytotoxic functions, and suggest technical improvements for future investigations.