Indirubin, a Chinese anti-leukaemia drug, promotes neutrophilic differentiation of human myelocytic leukaemia HL-60 cells
Indirubin, a Chinese anti-leukaemia drug, promotes neutrophilic differentiation of human myelocytic leukaemia HL-60 cells
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DOI：
10.1111/j.1365-2141.2005.05655.x
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发表时间：
2005-09-01
影响因子：
6.5
通讯作者：
Kasahara, T
中科院分区：
文献类型：
--
作者：
Suzuki, K;Adachi, R;Kasahara, T
靛玉红是一种紫色植物染料，是治疗髓细胞白血病的传统中药。靛玉红抑制细胞周期蛋白依赖性蛋白激酶（CDK），存在于人尿液和血清中。当靛玉红存在于人髓细胞白血病HL-60细胞的嗜酸性分化过程中时，它增强了终末分化的HL-60细胞由调理酵母聚糖（OZ）引发的超氧化物的产生。增强OZ对HL-60细胞内钙离子的反应，增强IL-8、CXCL-8和甲酰肽诱导的HL-60细胞趋化性。此外，靛玉红诱导细胞在分化过程中释放显著的IL-8，用靛玉红分化的细胞具有典型的嗜酸性，核和颗粒变形。使用含有报告载体的稳定克隆HL-60细胞来监测转录因子PU.1的活性，该转录因子PU.1特异性地作用于早幼粒细胞分化成中性粒细胞和单核细胞的阶段，揭示了靛玉红对细胞内PU.1具有有效的促进活性。靛玉红增强了典型的中性粒细胞蛋白质的表达，包括粒细胞集落刺激因子受体、β（2）-整联蛋白亚基CD 18、NADPH氧化酶亚基p47 phox和IL-8受体CXCR 1，所有这些蛋白质都受PU.1的控制。靛玉红也抑制CDK 2依赖性的视网膜母细胞瘤蛋白的磷酸化过程中的嗜酸性分化。这些结果表明靛玉红通过抑制CDK 2和激活PU.1来增强人髓细胞白血病HL-60细胞的嗜酸性分化。
Indirubin, a purple vegetable dye, is a traditional Chinese medicine for myelocytic leukaemia. Indirubin inhibits cyclin-dependent protein kinases (CDKs) and is present in human urine and serum. When indirubin was present during the neutrophilic differentiation of human myelocytic leukaemia HL-60 cells, it augmented superoxide production triggered by opsonized zymosan (OZ) by the terminally differentiated HL-60 cells. It also augmented the calcium response to OZ stimulation, and HL-60 cell chemotaxis evoked by interleukin-8 (IL-8, CXCL8) and formylpeptide. In addition, indirubin induced marked IL-8 release by the cells during differentiation and the cells differentiated with indirubin had typical neutrophilic properties, deformed nuclei and granules. Use of stable cloned HL-60 cells that contained a reporter vector for monitoring the activity of the transcription factor PU.1, which acts specifically at the stage of promyelocyte differentiation into neutrophils and monocytes, revealed that indirubin has a potent promoting activity on intracellular PU.1. Indirubin enhanced the expression of typical neutrophil proteins, including granulocyte-colony stimulating factor receptor, the beta(2)-integrin subunit CD18, the NADPH-oxidase subunit p47phox, and the IL-8 receptor CXCR1, all are controlled by PU.1. Indirubin also inhibited CDK2-dependent phosphorylation of retinoblastoma protein during neutrophilic differentiation. These results suggest that indirubin augments the neutrophilic differentiation of human myelocytic leukaemia HL-60 cells through inhibition of CDK2 and activation of PU.1.