EFFECT OF INTERLEUKIN-1-BETA CONVERTING-ENZYME-INHIBITOR ON ACUTE MYELOGENOUS LEUKEMIA PROGENITOR PROLIFERATION
EFFECT OF INTERLEUKIN-1-BETA CONVERTING-ENZYME-INHIBITOR ON ACUTE MYELOGENOUS LEUKEMIA PROGENITOR PROLIFERATION
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DOI：
10.1182/blood.v86.12.4594.bloodjournal86124594
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发表时间：
1995-12-15
期刊：
影响因子：
20.3
通讯作者：
TALPAZ, M
中科院分区：
文献类型：
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作者：
ESTROV, Z;BLACK, RA;TALPAZ, M
白细胞介素-1 β（IL-1 β）转化酶（ICE）是一种半胱氨酸蛋白酶，其特异性地将前体IL-1 β切割成其生物活性形式。最近的研究还表明ICE在脊椎动物细胞中诱导凋亡。由于IL-1在急性髓细胞白血病（AML）母细胞增殖中起主要作用，我们试图研究ICE抑制对AML祖细胞的影响。为此，我们使用了bocaspartyl（benzyl）chloromethylketone（BACMK），这是一种旨在穿透细胞并与ICE的活性位点共价结合的抑制剂。我们的初步实验表明，活化的外周血细胞与2.5 μ mol/L的BAMCK孵育下调成熟IL-1 β的产生，但对肿瘤坏死因子-ct没有影响。为了测试抑制剂对AML细胞的作用，我们首先使用OCI/AML 3细胞系。我们发现这些细胞产生IL-1 β并结合生物素化的细胞因子，并且IL-1抑制剂，如IL-1中和抗体、IL-1受体拮抗剂和可溶性IL-1受体，特异性抑制OCI/AML 3增殖，表明IL-1 β是OCI/AML 3细胞的自分泌生长因子。ICE抑制剂以剂量依赖性方式（0.4 - 4 μ mol/L）抑制OCI/AML 3生长，并下调成熟IL-1 β的产生，如Western免疫印迹法所评估。从16例AML患者的骨髓穿刺液中获得了类似的结果。ICE抑制剂在0.4 - 5 μ mol/L浓度范围内以剂量依赖性方式抑制AML前体细胞的增殖（高达78%;平均44%），但不抑制正常骨髓祖细胞的增殖; IL-1 β可逆转抑制作用。此外，AML细胞与4 μ mol/L BAMCK的孵育下调成熟IL-1 β的产生，表明生长抑制作用是通过抑制生物活性细胞因子介导的。我们的数据表明，ICE抑制抑制AML母细胞增殖，并表明ICE抑制剂可能在未来的AML治疗中发挥作用。(C)1995年，美国血液学会。
Interleukin-1 beta (IL-1 beta) converting enzyme (ICE) is a cysteine protease that specifically cleaves precursor IL-1 beta to its biologically active form. Recent studies have also implicated ICE in the induction of apoptosis in vertebrate cells. Because IL-1 plays a major role in acute myelogenous leukemia (AML) blast proliferation, we sought to investigate the effect of ICE inhibition on AML progenitors. To do this, we used bocaspartyl (benzyl) chloromethylketone (BACMK) an inhibitor designed to penetrate cells and bind covalently to the active site of ICE. Our preliminary experiments showed that incubation of activated peripheral blood cells with 2.5 mu mol/L of BAMCK downregulated production of mature IL-1 beta but had no effect on tumor necrosis factor-ct. To test the effects of the inhibitor on AML cells, we first used the OCI/AML3 cell line. We found that these cells produce IL-1 beta and bind the biotinylated cytokine and that IL-1 inhibitors, such as IL-1 neutralizing antibodies, IL-1 receptor antagonist, and soluble IL-1 receptors, specifically inhibit OCI/AML3 proliferation, indicating that IL-1 beta is an autocrine growth factor for OCI/AML3 cells. The ICE inhibitor suppressed OCI/AML3 growth in a dose-dependent manner (at 0.4 to 4 mu mol/L) and downregulated mature IL-1 beta production, as assessed by Western immunoblotting. Similar results were obtained with marrow aspirates from 16 AML patients. The ICE inhibitor suppressed proliferation of AML precursors (by up to 78%; mean, 44%) in a dose-dependent fashion at concentrations ranging from 0.4 to 5 mu mol/L but not proliferation of normal marrow progenitors; the suppressive effect was reversed by IL-1 beta. Furthermore, incubation of AML cells with 4 mu mol/L BAMCK downregulated the production of mature IL-1 beta, suggesting that the growth-inhibitory effect is mediated through suppression of the biologically active cytokine. Our data indicate that inhibition of ICE suppresses AML blast proliferation and suggest that ICE inhibitors may have a role in future therapies for AML. (C) 1995 by The American Society of Hematology.