Functional role of kallikrein 6 in regulating immune cell survival.
Functional role of kallikrein 6 in regulating immune cell survival.
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DOI：
10.1371/journal.pone.0018376
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发表时间：
2011-03-28
期刊：
影响因子：
3.7
通讯作者：
Bryson AL
中科院分区：
文献类型：
--
作者：
Scarisbrick IA;Epstein B;Cloud BA;Yoon H;Wu J;Renner DN;Blaber SI;Blaber M;Vandell AG;Bryson AL
激肽释放酶6（KLK 6）是分泌型丝氨酸蛋白酶的激肽释放酶家族的新鉴定的成员，先前的研究表明其在中枢神经系统（CNS）炎症部位升高，并且其显示出随着T细胞活化而调节的表达。值得注意的是，多发性硬化症（MS）患者的血清中KLK 6也升高，但其在免疫功能中的潜在作用尚不清楚。在这里，我们专门研究KLK 6是否改变免疫细胞的存活以及可能发生的可能机制。使用小鼠全脾细胞制剂和人Jurkat T细胞系，我们证明KLK 6在一系列细胞死亡范例中有力地支持细胞存活。重组KLK 6显示出在静息条件下以及响应于喜树碱、地塞米松、星形孢菌素和Fas-配体而显著减少细胞死亡。此外，Jurkat T细胞中的KLK 6过表达显示产生平行的促存活效应。在混合的脾细胞群中，KLK 6的强有力的免疫细胞存活促进作用显示为包括T和B淋巴细胞，仅用5分钟的处理就发生，并且涉及促存活蛋白B细胞淋巴瘤-特大型（Bcl-XL）的上调，和促凋亡蛋白Bcl-2相互作用的细胞死亡介质（Bim）的抑制。KLK 6促进脾T细胞存活的能力也显示在来自PAR 1缺陷小鼠的细胞制备物中不存在。KLK 6通过部分依赖于PAR 1活化的机制促进淋巴细胞存活。这些发现指出了一种调节淋巴细胞存活的新分子机制，该机制可能与依赖于细胞凋亡的免疫清除和维持稳态的一系列免疫应答相关。
Kallikrein 6 (KLK6) is a newly identified member of the kallikrein family of secreted serine proteases that prior studies indicate is elevated at sites of central nervous system (CNS) inflammation and which shows regulated expression with T cell activation. Notably, KLK6 is also elevated in the serum of multiple sclerosis (MS) patients however its potential roles in immune function are unknown. Herein we specifically examine whether KLK6 alters immune cell survival and the possible mechanism by which this may occur. Using murine whole splenocyte preparations and the human Jurkat T cell line we demonstrate that KLK6 robustly supports cell survival across a range of cell death paradigms. Recombinant KLK6 was shown to significantly reduce cell death under resting conditions and in response to camptothecin, dexamethasone, staurosporine and Fas-ligand. Moreover, KLK6-over expression in Jurkat T cells was shown to generate parallel pro-survival effects. In mixed splenocyte populations the vigorous immune cell survival promoting effects of KLK6 were shown to include both T and B lymphocytes, to occur with as little as 5 minutes of treatment, and to involve up regulation of the pro-survival protein B-cell lymphoma-extra large (Bcl-XL), and inhibition of the pro-apoptotic protein Bcl-2-interacting mediator of cell death (Bim). The ability of KLK6 to promote survival of splenic T cells was also shown to be absent in cell preparations derived from PAR1 deficient mice. KLK6 promotes lymphocyte survival by a mechanism that depends in part on activation of PAR1. These findings point to a novel molecular mechanism regulating lymphocyte survival that is likely to have relevance to a range of immunological responses that depend on apoptosis for immune clearance and maintenance of homeostasis.
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