Mesenchymal Stem Cells Tune the Development of Monocyte-Derived Dendritic Cells Toward a Myeloid-Derived Suppressive Phenotype through Growth-Regulated Oncogene Chemokines
Mesenchymal Stem Cells Tune the Development of Monocyte-Derived Dendritic Cells Toward a Myeloid-Derived Suppressive Phenotype through Growth-Regulated Oncogene Chemokines
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DOI：
10.4049/jimmunol.1202775
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发表时间：
2013-05-15
影响因子：
4.4
通讯作者：
Hsu, Shu-Ching
中科院分区：
文献类型：
--
作者：
Chen, Hsin-Wei;Chen, Hsin-Yu;Hsu, Shu-Ching
骨髓间充质干/基质细胞（Mesenchymal stem/stromal cells，MSCs）具有免疫抑制功能，是治疗免疫性疾病的潜在候选细胞。然而，介导MSC免疫抑制活性的分子机制仍然难以捉摸。在这篇文章中，我们报告的第一次，据我们所知，分泌的生长调节癌基因（GRO）趋化因子，特别是GRO-γ，在人MSC条件培养基的分化和人单核细胞来源的树突状细胞的功能的影响。单核细胞来源的树突状细胞被GRO趋化因子驱动向骨髓来源的抑制细胞（MDSC）样表型。GRO-γ处理的MDSC具有致耐受性表型，其特征在于IL-10和IL-4的分泌增加以及IL-12和IFN-γ的产生减少。我们还表明，MDSC的特征性标志物-β-淀粉酶-1和诱导型NO合酶基因的mRNA表达水平被GRO-γ引发的小鼠骨髓细胞上调。此外，GRO-γ处理的骨髓来源的树突状细胞刺激OVA特异性CD 8（+）T（OT-1）细胞增殖的能力以及IFN-γ和TNF-α的细胞因子产生在体内显著降低。我们的研究结果使人们更好地了解MDSC是如何产生的，并提供了新的视角，以利用MDSC的潜力作为治疗慢性炎症和自身免疫以及预防移植排斥的替代方法。
Mesenchymal stem/stromal cells (MSCs) are promising potential candidates for the treatment of immunological diseases because of their immunosuppressive functions. However, the molecular mechanisms that mediate MSCs' immunosuppressive activity remain elusive. In this article, we report for the first time, to our knowledge, that secreted growth-regulated oncogene (GRO) chemokines, specifically GRO-gamma, in human MSC-conditioned media have an effect on the differentiation and the function of human monocyte-derived dendritic cells. The monocyte-derived dendritic cells were driven toward a myeloid-derived suppressor cell (MDSC)-like phenotype by the GRO chemokines. GRO-gamma-treated MDSCs had a tolerogenic phenotype that was characterized by an increase in the secretion of IL-10 and IL-4, and a reduction in the production of IL-12 and IFN-gamma. We have also shown that the mRNA expression levels of the arginase-1 and inducible NO synthase genes, which characterize MDSCs, were upregulated by GRO-gamma-primed mouse bone marrow cells. In addition, the ability of GRO-gamma-treated bone marrow-derived dendritic cells to stimulate the OVA-specific CD8(+) T (OT-1) cell proliferation and the cytokine production of IFN-gamma and TNF-alpha were significantly decreased in vivo. Our findings allow a greater understanding of how MDSCs can be generated and offer new perspectives to exploit the potential of MDSCs for alternative approaches to treat chronic inflammation and autoimmunity, as well as for the prevention of transplant rejection.