Interferon-γ impairs proliferation of hematopoietic stem cells in mice
Interferon-γ impairs proliferation of hematopoietic stem cells in mice
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DOI：
10.1182/blood-2012-05-432906
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发表时间：
2013-05-02
期刊：
影响因子：
20.3
通讯作者：
Nolte, Martijn A.
中科院分区：
文献类型：
--
作者：
de Bruin, Alexander M.;Demirel, Ozlem;Nolte, Martijn A.
平衡造血干细胞(HSC)分化和自我更新的过程对于维持终生血细胞供应至关重要。骨髓(BM)能产生稳定的新生成细胞，但免疫应激条件引起的白细胞减少增加了对外周血细胞供应的需求。在这里，我们证明了促炎细胞因子干扰素-γ通过直接降低HSC的增殖能力来损害HSC的维持，并且在病毒感染后，干扰素-γ损害了HSC数量的恢复。我们发现，干扰素-γ降低了血小板生成素(TPO)介导的信号转导和转录激活因子(STAT)5的磷酸化，STAT是HSC自我更新的重要正向调节因子。干扰素-γ还可诱导HSC中细胞因子信号转导抑制因子(SOCS)1的表达，我们证明SOCS1的表达足以抑制TPO诱导的STAT5磷酸化。此外，干扰素-γ解除了STAT5介导的细胞周期基因cyClind1和p57的表达调控。这些发现表明，干扰素-γ通过改变细胞因子反应和参与HSC增殖的基因表达，是HSC自我更新的负性调节因子。我们推测，在慢性炎症条件下，如再生障碍性贫血、HIV和移植物抗宿主病，骨髓衰竭的发生与这些疾病中慢性干扰素-γ信号导致的HSC自我更新的持续损害有关。
Balancing the processes of hematopoietic stem cell (HSC) differentiation and self-renewal is critical for maintaining a lifelong supply of blood cells. The bone marrow (BM) produces a stable output of newly generated cells, but immunologic stress conditions inducing leukopenia increase the demand for peripheral blood cell supply. Here we demonstrate that the proinflammatory cytokine interferon-gamma (IFN-gamma) impairs maintenance of HSCs by directly reducing their proliferative capacity and that IFN-gamma impairs restoration of HSC numbers upon viral infection. We show that IFN-gamma reduces thrombopoietin (TPO)-mediated phosphorylation of signal transducer and activator of transcription (STAT) 5, an important positive regulator of HSC self-renewal. IFN-gamma also induced expression of suppressor of cytokine signaling (SOCS) 1 in HSCs, and we demonstrate that SOCS1 expression is sufficient to inhibit TPO-induced STAT5 phosphorylation. Furthermore, IFN-gamma deregulates expression of STAT5-mediated cell-cycle genes cyclin D1 and p57. These findings suggest that IFN-gamma is a negative modulator of HSC self-renewal by modifying cytokine responses and expression of genes involved in HSC proliferation. We postulate that the occurrence of BM failure in chronic inflammatory conditions, such as aplastic anemia, HIV, and graft-versus-host disease, is related to a sustained impairment of HSC self-renewal caused by chronic IFN-gamma signaling in these disorders.