Upregulation of lipocortin 1 inhibits tumour necrosis factor‐induced apoptosis in human leukaemic cells: a possible mechanism of resistance to immune surveillance
Upregulation of lipocortin 1 inhibits tumour necrosis factor‐induced apoptosis in human leukaemic cells: a possible mechanism of resistance to immune surveillance
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DOI：
10.1111/j.1365-2141.2000.02397.x
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发表时间：
2000-12
影响因子：
6.5
通讯作者：
Yu-Ling Wu;Xu‐Rong Jiang;D. Lillington;A. Newland;S. Kelsey
中科院分区：
文献类型：
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作者：
Yu-Ling Wu;Xu‐Rong Jiang;D. Lillington;A. Newland;S. Kelsey
肿瘤坏死因子诱导白血病细胞凋亡的信号转导途径可能涉及胞浆磷脂酶A2的激活。类固醇激素地塞米松(Dex)和1，25(OH)2 D3均可使U937白血病细胞对肿瘤坏死因子诱导的细胞凋亡产生抵抗。在这项研究中，我们发现地塞米松抑制了cPLA2的自发激活和肿瘤坏死因子诱导的激活。地塞米松对细胞内cPLA2水平无直接影响，但在随后用肿瘤坏死因子刺激细胞时促进cPLA2的降解。此外，地塞米松还增加了内源性cPLA2抑制物脂皮质素1(Lc1)的合成。针对Lc1的反义寡核苷酸可以完全消除地塞米松诱导的对肿瘤坏死因子细胞毒作用的抵抗。表现出对肿瘤坏死因子耐药的髓系白血病细胞系的组成性LC1水平相对高于对肿瘤坏死因子敏感的髓系白血病细胞系。我们的数据表明，地塞米松通过上调细胞内Lc1水平和促进负反馈循环来增强U937细胞对肿瘤坏死因子诱导的凋亡的抵抗力，该负反馈循环在受到肿瘤坏死因子刺激时被激活。白血病原始细胞中高组成水平的LC1可能会保护它们免受免疫介导的杀伤。
The signal transduction pathway through which tumour necrosis factor (TNF) induces apoptosis in leukaemic cells may involve activation of cytosolic phospholipase A2 (cPLA2). The steroids dexamethasone (Dex) and 1,25(OH)2 D3 both render U937 leukaemic cells resistant to TNF‐induced apoptosis. In this study, we found that Dex inhibited both spontaneous and TNF‐induced activation of cPLA2. Dex had no direct effect on cellular cPLA2 levels, but facilitated cPLA2 degradation upon subsequent stimulation of cells with TNF. In addition, Dex increased synthesis of the endogenous cPLA2 inhibitor lipocortin 1 (LC1). An antisense oligonucleotide to LC1 could completely abrogate Dex‐induced resistance to the cytotoxic action of TNF. Constitutive LC1 levels were relatively higher in myeloid leukaemic blasts showing resistance to TNF than TNF‐sensitive myeloid leukaemic cell lines. Our data suggest that Dex confers the resistance of U937 cells to TNF‐induced apoptosis by upregulating intracellular levels of LC1 and by facilitating a negative‐feedback loop, which is activated upon stimulation with TNF. High constitutive levels of LC1 in leukaemic blasts may protect them against immune‐mediated killing.