Notch-RBP-J signaling is required by bone marrow stromal cells for the treatment of acute graft versus host disease.
Notch-RBP-J signaling is required by bone marrow stromal cells for the treatment of acute graft versus host disease.
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DOI：
10.1016/j.scr.2013.04.009
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发表时间：
2013-09
影响因子：
1.2
通讯作者：
Yaochun Wang;Shu-hong Wang;Ya-Ning Wei;D. Du;Hao Xu;Chun-chen Gao;M. Zheng;Juan Xie;Jun-Chang Li;Guang-ying Dong;Li Li-Li;Yange Xiao;Hua Han
中科院分区：
文献类型：
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作者：
Yaochun Wang;Shu-hong Wang;Ya-Ning Wei;D. Du;Hao Xu;Chun-chen Gao;M. Zheng;Juan Xie;Jun-Chang Li;Guang-ying Dong;Li Li-Li;Yange Xiao;Hua Han
最近的证据表明，骨髓基质细胞（BMSCs）可能通过可溶性介质和直接细胞-细胞接触表现出免疫抑制活性，但这些过程是如何调节的一直知之甚少。在这项研究中，我们表明，Notch信号通路参与了骨髓基质细胞的调制，引发其免疫抑制作用。在小鼠致死性急性移植物抗宿主病（aGvHD）模型中，RBP-J（介导来自所有四种哺乳动物Notch受体的信号传导的关键转录因子）缺陷的BMSC未能延迟疾病的发展。RBP-J缺陷BMSCs不能抑制同种异体T细胞的增殖和活化。RBP-J缺陷BMSCs不能下调树突状细胞（DCs）表面MHC Ⅱ类分子和共刺激分子CD 80、CD 86的表达。与野生型BMSC相比，与RBP-J缺陷型BMSC共培养的DC的抗原呈递能力没有受损。此外，我们发现，IL-6和PGE 2，两个关键分子介导的BMSCs的免疫抑制活性，在RBP-J缺陷的BMSCs的生产显着减少。这两种分子均通过Notch信号通路参与BMSCs的调控。总之，我们的数据表明，骨髓间充质干细胞在aGvHD中的免疫抑制作用依赖于Notch-RBP-J信号传导，其调节IL-6和PGE 2的产生。
Recent evidence has shown that bone marrow stromal cells (BMSCs) may exhibit immuno-suppression activities through soluble mediators and direct cell–cell contact, but how these processes are modulated has been poorly understood. In this study, we show that the Notch signaling pathway participates in the modulation of BMSCs to elicit their immuno-suppressive roles. In a murine lethal acute graft versus host disease (aGvHD) model, BMSCs deficient for RBP-J, the critical transcription factor mediating signaling from all four mammalian Notch receptors, failed to delay the development of the disease. RBP-J deficient BMSCs were not able to inhibit the proliferation and activation of allogenic T-cells. Moreover, RBP-J deficient BMSCs could not down-regulate the expression of MHC II and co-stimulation molecules CD80 and CD86 on dendritic cells (DCs). The antigen presentation capacity of DCs co-cultured with RBP-J deficient BMSCs was not impaired in contrast to wild type BMSCs. Furthermore, we showed that the productions of IL-6 and PGE2, two critical molecules mediating the immuno-suppressive activities of BMSCs, were reduced significantly in RBP-J deficient BMSCs. Both of the two molecules were importantly involved in the regulation of BMSCs by Notch signaling. In conclusion, our data suggests that the immuno-suppressive effects of BMSCs in aGvHD are dependent on Notch-RBP-J signaling, which regulates the productions of IL-6 and PGE2.