Involvement of cyclin D3, CDKN1A (p21), and BIRC5 (Survivin) in interleukin 11 stimulation of decidualization in mice
Involvement of cyclin D3, CDKN1A (p21), and BIRC5 (Survivin) in interleukin 11 stimulation of decidualization in mice
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DOI：
10.1095/biolreprod.107.063313
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发表时间：
2008-01-01
影响因子：
3.6
通讯作者：
Gibori, Geula
中科院分区：
文献类型：
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作者：
Li, Feixue;Devi, Y. Sangeeta;Gibori, Geula
白细胞介素11受体α（ILI1ra）无效的小鼠由于蜕膜化缺陷和异常滋养层侵入而不育。我们以前在这些小鼠中发现，蜕膜蛋白酶抑制剂的下调在不受控制的滋养层侵袭中起作用。然而，蜕膜是异常较小的假孕Il11ra裸小鼠，滋养层浸润不是一个因素。在这里，我们研究是否有缺陷的蜕膜化是由于参与蜕膜细胞生长和分化的关键分子的失调。我们发现了一个显着下调细胞周期蛋白D3在Il11ra裸小鼠。我们还发现，IL 11强烈刺激细胞培养物中细胞周期蛋白D3的表达。CDK4和CDK6，细胞周期蛋白D3的已知伙伴，不受影响。免疫定位研究表明，在子宫系膜部位的细胞周期蛋白D3和分化的多倍体细胞的情况下，在反子宫系膜部位的Il11ra空小鼠的情况下。我们还检测了细胞分化因子CDKN 1 A（p21）和CDKN 1 B（p27）的表达，并且发现在体内和细胞培养中，CDKN 1 A（p21）的表达而不是CDKN 1 B（p27）的表达受IL 11的控制。IL 11在蜕膜中的另一个明确的靶点是BIRC 5（存活素），其表达在IL 11ra缺失小鼠的蜕膜中被抑制，并在细胞培养物中被IL 11刺激。总之，这些结果至少部分地解释了缺乏Il11ra基因的小鼠的有缺陷的小蜕膜，并首次揭示了细胞周期蛋白133、CDKN1A（p2l）和BIRC 5（Survivin）是蜕膜中IL 11的靶点。
Interleukin 11 receptor alpha (IlI 1ra) null mice are infertile due to defective decidualization and abnormal trophoblast invasion. We have previously shown in these mice that downregulation of decidual proteinase inhibitors plays a role in uncontrolled trophoblast invasion. However, the decidua is abnormally smaller in pseudopregnant Il11ra null mice, where trophoblast invasion is not a factor. Here, we examined whether defective decidualization is due to dysregulation of key molecules involved in decidual cell growth and differentiation. We found a dramatic downregulation of cyclin D3 in Il11ra null mice. We also found that IL11 robustly stimulates the expression of cyclin D3 in cell culture. CDK4 and CDK6, known partners of cyclin D3, are not affected. Immunolocalizalion studies show absence of cyclin D3 in the mesometrial site and absence of differentiated polyploid cells in the anti mesometrial site of Il11ra null mice. We also examined the expression of cell differentiation factors CDKN1 A (p21) and CDKN1 B (p27), and found that in both in vivo and cell culture the expression of CDKN1A (p21) but not CDKN1B (p27) is under the control of Il11. Another clear target of IL11 in the decidua is BIRC5 (Survivin), whose expression is repressed in the decidua of Il11ra null mice and stimulated by IL11 in cell culture. Taken together, these results provide, at least in part, an explanation for the defective small decidua of mice lacking the Il11ra gene, and reveal for the first time that cyclin 133, CDKN1A (p2l), and BIRC5 (Survivin) are targets of IL11 in the decidua.