The proinflammatory cytokine GM-CSF downregulates fetal hemoglobin expression by attenuating the cAMP-dependent pathway in sickle cell disease
The proinflammatory cytokine GM-CSF downregulates fetal hemoglobin expression by attenuating the cAMP-dependent pathway in sickle cell disease
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DOI：
10.1016/j.bcmd.2011.08.005
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发表时间：
2011-12-15
影响因子：
2.3
通讯作者：
Head, C. Alvin
中科院分区：
文献类型：
--
作者：
Ikuta, Tohru;Adekile, Adekunle D.;Head, C. Alvin
虽然镰状细胞病（SCD）患者羟基脲治疗后白细胞计数减少可预测胎儿血红蛋白（HbF）反应，但其潜在机制尚不清楚。我们之前报道过SCD患者的白细胞计数受粒细胞-巨噬细胞集落刺激因子（GM-CSF）的调节。在这里，我们研究了GM-CSF在SCD中调节HbF表达的作用。通过对372例患者的回顾性数据分析，未经羟基脲治疗的SCD患者HbF水平与白细胞计数和GM-CSF水平呈负相关，而羟基脲治疗后HbF增加与白细胞计数减少相关，提示GM-CSF对HbF表达有负作用。与此一致的是，使用原代红母细胞的体外研究表明，将GM-CSF添加到红母细胞中可以降低HbF的表达。接下来，我们研究了GM-CSF降低HbF表达的细胞内信号通路。GM-CSF处理红细胞导致细胞内cAMP水平降低，cAMP反应元件结合蛋白磷酸化消失，表明cAMP依赖途径减弱，而丝裂原活化蛋白激酶的磷酸化水平不受影响。这与我们的研究一致，表明camp依赖通路在HbF表达中的作用。总之，这些结果表明GM-CSF在SCD中调节白细胞计数和HbF表达方面发挥作用。羟基脲治疗后GM-CSF水平的降低可能是有效诱导HbF的关键。显示GM-CSF参与HbF表达的结果可能提示SCD羟基脲耐药的可能机制。(C) 2011爱思唯尔公司版权所有。
Although reduction in leukocyte counts following hydroxyurea therapy in sickle cell disease (SCD) predicts fetal hemoglobin (HbF) response, the underlying mechanism remains unknown. We previously reported that leukocyte counts are regulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) in SCD patients. Here we examined the roles of GM-CSF in the regulation of HbF expression in SCD. Upon the analysis of retrospective data in 372 patients, HbF levels were inversely correlated with leukocyte counts and GM-CSF levels in SCD patients without hydroxyurea therapy, while HbF increments after hydroxyurea therapy correlated with a reduction in leukocyte counts, suggesting a negative effect of GM-CSF on HbF expression. Consistently, in vitro studies using primary erythroblasts showed that the addition of GM-CSF to erythroid cells decreased HbF expression. We next examined the intracellular signaling pathway through which GM-CSF reduced HbF expression. Treatment of erythroid cells with GM-CSF resulted in the reduction of intracellular cAMP levels and abrogated phosphorylation of cAMP response-element-binding-protein, suggesting attenuation of the cAMP-dependent pathway, while the phosphorylation levels of mitogen-activated protein kinases were not affected. This is compatible with our studies showing a role for the cAMP-dependent pathway in HbF expression. Together, these results demonstrate that GM-CSF plays a role in regulating both leukocyte count and HbF expression in SCD. Reduction in GM-CSF levels upon hydroxyurea therapy may be critical for efficient HbF induction. The results showing the involvement of GM-CSF in HbF expression may suggest possible mechanisms for hydroxyurea resistance in SCD. (C) 2011 Elsevier Inc. All rights reserved.