PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-2 INHIBITS TUMOR-NECROSIS-FACTOR-ALPHA-INDUCED APOPTOSIS - EVIDENCE FOR AN ALTERNATE BIOLOGICAL FUNCTION
PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-2 INHIBITS TUMOR-NECROSIS-FACTOR-ALPHA-INDUCED APOPTOSIS - EVIDENCE FOR AN ALTERNATE BIOLOGICAL FUNCTION
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DOI：
10.1074/jbc.270.46.27894
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发表时间：
1995-11-17
影响因子：
4.8
通讯作者：
ANTALIS, TM
中科院分区：
文献类型：
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作者：
DICKINSON, JL;BATES, EJ;ANTALIS, TM
纤溶酶原激活物抑制剂2型（派-2）是一种丝氨酸蛋白酶抑制剂或丝氨酸蛋白酶抑制剂，是巨噬细胞响应内毒素和炎性细胞因子的主要产物。我们探讨了派-2在肿瘤坏死因子α（TNF）引起的细胞凋亡中的作用。稳定转染派-2cDNA的HeLa细胞对TNF诱导的凋亡有保护作用，而转染反义派-2cDNA、对照基因或质粒载体的HeLa细胞则对TNF诱导的凋亡敏感。不同克隆的HeLa细胞表达派-2的水平与其对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。与此相反，派-2的表达并没有赋予保护对紫外线或电离辐射诱导的细胞凋亡。丝氨酸蛋白酶尿激酶型纤溶酶原激活剂未被证明是派-2作用的靶点。派-2的P-1-Arg氨基酸残基被确定为保护所需的，因为表达在该位置具有Ala的派-2的细胞不被保护免于TNF介导的细胞死亡。结果表明，细胞内派-2可能是一个重要的因素，在调节细胞死亡的TNF介导的炎症过程中，通过抑制蛋白酶参与TNF诱导的凋亡。
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 P-1-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.