Inhibition of human mast cell proliferation and survival by tamoxifen in association with ion channel modulation
Inhibition of human mast cell proliferation and survival by tamoxifen in association with ion channel modulation
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DOI：
10.1016/j.jaci.2003.07.004
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发表时间：
2003-11-01
影响因子：
14.2
通讯作者：
Bradding, P
中科院分区：
文献类型：
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作者：
Duffy, SM;Lawley, WJ;Bradding, P
背景：人肺肥大细胞（HLMCs）和人肥大细胞系HMC-1表达一种由电压依赖性Cl-通道CIC-5携带的强烈的向外整流Cl-电流特性。在星形胶质细胞中，一种类似但不同的电流被认为与细胞增殖的控制有关。目的：在本研究中，我们研究了Cl通道阻滞剂他莫昔芬对HMC-1和hmc细胞离子通道活性和细胞增殖的影响。方法：采用全细胞膜片钳技术，对添加他莫昔芬前后肥大细胞的宏观离子电流进行表征。通过氚化胸腺嘧啶的掺入评估HMC-1的增殖，通过长期培养计数细胞来评估HLMC的增殖，通过膜联蛋白V结合和碘化丙啶摄取来评估细胞活力。结果：在HMC-1中，在浓度为3 μ mol/L时，他莫昔芬使+130 mV向外的Cl-电流降低73% +/- 9%，同时在-130 mV下打开了一个新的向内整流非选择性阳离子电流，平均向内电流为153 18 pA。他莫昔芬对HMC-1增殖产生剂量依赖性抑制（30 μ mol/L时抑制90.3% +/- 4.0%），而不改变细胞活力。他莫昔芬抑制HLMC向外cic -5样电流，不打开向内电流，长期培养对HLMC增殖产生剂量依赖性抑制。结论：他莫昔芬可能通过离子通道调节抑制HMC增殖。这表明他莫昔芬可能对肥大细胞介导的疾病（包括肥大细胞增多症、哮喘和肺纤维化）的治疗有用。
Background: Human lung mast cells (HLMCs) and the human mast cell line HMC-1 express a strongly outwardly rectifying Cl- current characteristic of that carried by the voltage-dependent Cl- channel CIC-5. A similar but distinct current has been implicated in the control of cell proliferation in astrocytes.Objective: In this study, we have examined the effects of the Cl- channel blocker tamoxifen on ion channel activity and cell proliferation in both HMC-1 and HLMCs.Methods: We used the whole-cell patch-clamp technique to characterize macroscopic ion currents in mast cells before and after addition of tamoxifen. HMC-1 proliferation was assessed by incorporation of tritiated thymidine, HLMC proliferation was determined by counting cells in long-term culture, and cell viability was assessed by annexin V binding and propidium iodide uptake.Results: In HMC-1, tamoxifen reduced the outward Cl- current at +130 mV by 73% +/- 9% at a concentration of 3 mumol/L and simultaneously opened a novel inwardly rectifying nonselective cation current with a mean inward current of 153 18 pA at -130 mV. Tamoxifen produced a dose-dependent inhibition of HMC-1 proliferation (90.3% +/- 4.0% inhibition at 30 mumol/L) without altering cell viability. Tamoxifen inhibited the outward CIC-5-like current in HLMCs, did not open an inward current, and produced a dose-dependent inhibition of HLMC proliferation in long-term culture.Conclusion: Tamoxifen inhibits HMC proliferation, possibly through ion channel modulation. This suggests that tamoxifen might be useful in the treatment of mast-cell-mediated diseases, including mastocytosis, asthma, and pulmonary fibrosis.