Expression of high levels of human proteinase inhibitor 9 blocks both perforin/granzyme and Fas/Fas ligand-mediated cytotoxicity
Expression of high levels of human proteinase inhibitor 9 blocks both perforin/granzyme and Fas/Fas ligand-mediated cytotoxicity
复制标题
DOI：
10.1016/j.cellimm.2007.03.004
复制
发表时间：
2007-01-01
影响因子：
4.3
通讯作者：
Shapiro, David J.
中科院分区：
文献类型：
--
作者：
Cunningham, Thomas D.;Jiang, Xinguo;Shapiro, David J.
蛋白酶抑制剂 9（PI-9、SerpinB9）是唯一已知的人类细胞内颗粒酶 B 抑制剂。 PI-9 的表达是否足以阻止细胞毒性 T 淋巴细胞 (CTL) 和自然杀伤 (NK) 细胞诱导的细胞溶解仍然存在争议。为了评估 PI-9 的作用，我们分离并测试了三个稳定转染的细胞系。表达野生型 PI-9 的 HeLa 细胞和表达无活性突变体 PI-9 的细胞系。野生型 PI-9 的表达（而非无活性的突变体 PI-9）抑制人 NK92 和 NKL 自然杀伤细胞诱导的细胞溶解。因此，高水平 PI-9 的表达足以保护人类细胞免受 NK 细胞介导的细胞死亡。通过两项测定，我们发现表达野生型 PI-9（而非无活性突变体 PI-9）可阻断 Fas/Fas 配体 (Fas/FasL) 介导的细胞凋亡。 PI-9表达对依托泊苷诱导的细胞凋亡没有影响。对 Fas/FasL 介导的细胞凋亡表现出显着抗性的 HeLa 细胞的 PI-9 水平比 HCT116 人结肠癌细胞高 2 至 3 倍，比 MCF7/ERHA 乳腺癌细胞低 2 至 3 倍，其中 PI-9 受到雌激素和他莫昔芬的强烈诱导。靶细胞中 PI-9 表达水平的增加可能会通过穿孔素/颗粒酶途径，然后通过 Fas/FasL 途径阻断 NK 和 CTL 诱导的细胞毒性，从而逐渐抑制免疫监视。 (c) 2007 Elsevier Inc. 保留所有权利。
Proteinase inhibitor 9 (PI-9, SerpinB9) is the only known human intracellular granzyme B inhibitor. Whether expression of PI-9 is sufficient to block cytolysis induced by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells remains controversial. To evaluate the roles of PI-9, we isolated and tested three lines of stably transfected. HeLa cells expressing wild-type PI-9 and one line expressing an inactive mutant PI-9. Expressions of wild-type PI-9, but not the inactive mutant PI-9, inhibited cytolysis induced by human NK92 and NKL natural killer cells. Expression of high levels of PI-9 is therefore sufficient to protect human cells against NK cell-mediated cell death. Using two assays, we show that expressing wild-type PI-9, but not the inactive mutant PI-9, blocks Fas/Fas ligand (Fas/ FasL)-mediated apoptosis. PI-9 expression has no effect on etoposide-induced apoptosis. HeLa cells exhibiting substantial resistance to Fas/FasL-mediated apoptosis contain 2- to 3-fold higher PI-9 levels than HCT116 human colon cancer cells and 2- to 3-fold lower PI-9 levels than MCF7/ERHA breast cancer cells, in which PI-9 is strongly induced by estrogens, and by tamoxifen. Expression of increasing levels of PI-9 in target cells may progressively inhibit immune surveillance by blocking NK and CTL-induced cytotoxicity through the perforin/granzyme pathway and then through the Fas/FasL pathway. (c) 2007 Elsevier Inc. All rights reserved.