Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism
Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism
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DOI：
10.1634/stemcells.2006-0548
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发表时间：
2007-08-01
期刊：
影响因子：
5.2
通讯作者：
Noel, Daniele
中科院分区：
文献类型：
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作者：
Djouad, Farida;Charbonnier, Louis-Marie;Noel, Daniele
间充质干细胞（MSC）因其在组织工程中的潜在临床应用以及在同种异体移植中降低移植物抗宿主病的发生率和严重程度的能力而备受关注。我们先前已经表明，MSC介导的免疫抑制是通过刺激后诱导产生的可溶性因子的分泌来发挥作用的。本研究的目的是确定所涉及的分子及其潜在机制。我们发现小鼠MSC分泌高水平的白细胞介素（IL）-6和血管内皮生长因子，这与T细胞增殖的抑制直接相关。添加中和性抗IL - 6抗体或前列腺素E2抑制剂吲哚美辛后，T细胞活化部分恢复。有趣的是，在我们的实验条件下未检测到吲哚胺2,3 - 双加氧酶活性。相反，我们发现MSC降低成熟树突状细胞（DC）上主要组织相容性复合体II类、CD40和CD86共刺激分子的表达，这是导致T细胞增殖减少的原因。此外，我们发现骨髓祖细胞在MSC条件上清液中培养分化为DC的过程通过IL - 6的分泌而部分受到抑制。总之，这些数据表明IL - 6通过部分抑制DC分化参与了MSC介导的免疫调节机制，但可能不是主要机制。
Mesenchymal stem cells (MSC) are of particular interest for their potential clinical use in tissue engineering as well as for their capacity to reduce the incidence and severity of graft-versus-host disease in allogeneic transplantation. We have previously shown that MSC-mediated immune suppression acts via the secretion of soluble factor(s) induced upon stimulation. The aim of this study was to identify the molecule(s) involved and the underlying mechanism(s). We show that murine MSC secrete high levels of interleukin (IL)-6 and vascular endothelial growth factor, which are directly correlated to the inhibition of T-cell proliferation. The T-cell activation is partially restored upon addition of a neutralizing anti-IL-6 antibody or the prostaglandin E2 inhibitor indomethacin. Interestingly, no indoleamine 2,3-dioxygenase activity was detected in our conditions. Instead, we show that MSC reduce the expression of major histocompatibility complex class 11, CD40, and CD86 costimulatory molecules on mature dendritic cells (DC), which was responsible for a decrease in T-cell proliferation. Moreover, we show that the differentiation of bone marrow progenitors into DC cultured with conditioned supernatants from MSC was partly inhibited through the secretion of IL-6. Altogether, these data suggest that IL-6 is involved in the immunoregulatory mechanism mediated by MSC through a partial inhibition of DC differentiation but is probably not the main mechanism.