Dickinson J L, Bates E J, Ferrante A, Antalis T M
Queensland Cancer Fund Experimental Oncology Unit, Queensland Institute of Medical Research, Brisbane, Australia.
J Biol Chem. 1995 Nov 17;270(46):27894-904. doi: 10.1074/jbc.270.46.27894.
Plasminogen activator inhibitor type 2 (PAI-2) is a serine proteinase inhibitor or serpin that is a major product of macrophages in response to endotoxin and inflammatory cytokines. We have explored the role of PAI-2 in apoptotic cell death initiated by tumor necrosis factor alpha (TNF). HeLa cells stably transfected with PAI-2 cDNA were protected from TNF-induced apoptosis, whereas cells transfected with antisense PAI-2 cDNA, a control gene, or the plasmid vector alone remained susceptible. The level of PAI-2 expressed by different HeLa cell clones was inversely correlated with their sensitivity to TNF. Loss of TNF sensitivity was not a result of loss of TNF receptor binding. In contrast, PAI-2 expression did not confer protection against apoptosis induced by ultraviolet or ionizing radiation. The serine proteinase urokinase-type plasminogen activator was not demonstrated to be the target of PAI-2 action. The P1-Arg amino acid residue of PAI-2 was determined to be required for protection, because cells expressing PAI-2 with an Ala in this position were not protected from TNF-mediated cell death. The results suggest that intracellular PAI-2 might be an important factor in regulating cell death in TNF-mediated inflammatory processes through inhibition of a proteinase involved in TNF-induced apoptosis.
纤溶酶原激活物抑制剂2（PAI - 2）是一种丝氨酸蛋白酶抑制剂或丝氨酸蛋白酶抑制因子，是巨噬细胞对内毒素和炎性细胞因子作出反应的主要产物。我们探讨了PAI - 2在肿瘤坏死因子α（TNF）引发的凋亡性细胞死亡中的作用。稳定转染PAI - 2 cDNA的HeLa细胞受到保护，免受TNF诱导的凋亡，而转染反义PAI - 2 cDNA、对照基因或单独质粒载体的细胞仍然敏感。不同HeLa细胞克隆表达的PAI - 2水平与它们对TNF的敏感性呈负相关。TNF敏感性的丧失不是TNF受体结合丧失的结果。相反，PAI - 2的表达并未赋予对紫外线或电离辐射诱导的凋亡的保护作用。丝氨酸蛋白酶尿激酶型纤溶酶原激活物未被证明是PAI - 2作用的靶点。已确定PAI - 2的P1 - Arg氨基酸残基是保护所必需的，因为在该位置表达带有丙氨酸的PAI - 2的细胞不能免受TNF介导的细胞死亡。结果表明，细胞内PAI - 2可能是通过抑制参与TNF诱导凋亡的蛋白酶，在TNF介导的炎症过程中调节细胞死亡的一个重要因素。
