Early Growth Response-2 Signaling Mediates Immunomodulatory Effects of Human Multipotential Stromal Cells
Early Growth Response-2 Signaling Mediates Immunomodulatory Effects of Human Multipotential Stromal Cells
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DOI：
10.1089/scd.2013.0194
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发表时间：
2014-01-15
影响因子：
4
通讯作者：
Tamama, Kenichi
中科院分区：
文献类型：
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作者：
Barbeau, Dominique J.;La, Kiet Tran;Tamama, Kenichi
虽然大多数研究表明多潜能基质细胞或间充质干细胞(MSC)疗法对免疫介导性疾病有用，但一些研究并未完全复制MSCs的免疫调节作用，这表明有必要确定MSCs在免疫反应调节中的潜在机制，以最大限度地发挥其免疫调节作用。我们发现转录因子早期生长反应基因-2(EGR2)是一种新的分子开关，调节人骨髓间充质干细胞中已知的免疫调节分子。EGR2结合于这些基因的启动子区域，即白介素6(IL6)、白血病抑制因子(LIF)、吲哚胺双加氧酶-1(IDO1)和环氧合酶-2/前列腺素-内源性过氧化物合成酶2(COX2/Ptgs2)，针对EGR2的siRNA被证明下调了这些基因的表达，并减少了COX2/Ptgs2下游产生的免疫调节介质前列腺素E2的产生。此外，EGR2基因敲除可恢复因MSC共培养而减少的T淋巴细胞增殖。因此，EGR2是优化基于MSC的治疗免疫调节特性的潜在靶点。
While most studies have suggested multipotential stromal cell or mesenchymal stem cell (MSC) therapies are useful for immune-mediated diseases, MSCs' immunomodulatory effects were not entirely reproduced in some studies, indicating the necessity to determine the underlying mechanism of MSCs' effects on immune response regulation to maximize their immunomodulatory effects. We have identified the transcription factor early growth response gene-2 (EGR2) as a novel molecular switch regulating known immunomodulatory molecules in human MSCs. EGR2 binds to the promoter regions of these genes, interleukin-6 (IL6), leukemia inhibitory factor (LIF), indoleamine dioxygenase-1 (IDO1), and cyclooxygenase-2/prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), and siRNA against EGR2 was shown to downregulate these genes and reduce the production of prostaglandin E2, an immunomodulatory mediator produced downstream of COX2/PTGS2. Moreover, EGR2 knockdown restores T-lymphocyte proliferation reduced by MSC coculture. Therefore, EGR2 is a potential target for the optimization of immunomodulatory properties of MSC-based therapies.