miR126 positively regulates mast cell proliferation and cytokine production through suppressing Spred1
miR126 positively regulates mast cell proliferation and cytokine production through suppressing Spred1
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DOI：
10.1111/j.1365-2443.2011.01529.x
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发表时间：
2011-07-01
期刊：
影响因子：
2.1
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Ishizaki, Takuma;Tamiya, Taiga;Yoshimura, Akihiko
Spred1（Sprouty 相关 Ena/VASP 同源 1 结构域蛋白）已被确定为生长因子诱导的 ERK/丝裂原激活蛋白激酶激活的负调节因子。 Spred1 还被认为是 micro RNA-126 (miR126)（一种位于 Egfl7 基因内的 miRNA）的靶标，并通过其调节 VEGF 信号传导的作用参与血管发育的调节。在这项研究中，我们研究了 miR126 和 Spred1 在造血系统中的作用，因为 miR126 已被证明在白血病细胞中过度表达。在肥大细胞从骨髓细胞分化过程中，miR126 水平下调，而 Spred1 表达则相反上调。 miR126 的过表达抑制了原代骨髓细胞和 MC9 肥大细胞中 Spred1 的表达并增强了 ERK 活性，这与 Fc epsilon RI 介导的细胞因子产生升高有关。为了证实体内 Spred1 减少的效果，我们生成了造血细胞特异性 Spred1 条件敲除小鼠。这些小鼠表现出肥大细胞数量增加，并且 Spred1 缺陷的骨髓来源的肥大细胞通过 Fc epsilon R 刺激的交联以及 IL-3 和 SCF 刺激而被高度激活。这些结果表明 Spred1 负向调节肥大细胞激活，而肥大细胞激活受 miR126 调节。
The protein known as Spred1 (Sprouty-related Ena/VASP homology-1 domain-containing protein) has been identified as a negative regulator of growth factor-induced ERK/mitogen-activated protein kinase activation. Spred1 has also been implicated as the target of micro RNA-126 (miR126), a miRNA located within the Egfl7 gene, and is involved in the regulation of vessel development through its role in regulating VEGF signaling. In this study, we examined the role of miR126 and Spred1 in the hematopoietic system, as miR126 has been shown to be overexpressed in leukemic cells. miR126 levels were down-regulated during mast cell differentiation from bone marrow cells, whereas Spred1 expression was inversely up-regulated. Overexpression of miR126 suppressed Spred1 expression and enhanced ERK activity in primary bone marrow cells and MC9 mast cells, which were associated with elevated Fc epsilon RI-mediated cytokine production. To confirm the effect of Spred1 reduction in vivo, we generated hematopoietic cell-specific Spred1-conditional knockout mice. These mice showed increased numbers of mast cells, and Spred1-deficient bone marrow-derived mast cells were highly activated by cross-linking of Fc epsilon R stimulation as well as by IL-3 and SCF stimulation. These results suggest that Spred1 negatively regulates mast cell activation, which is modulated by miR126.