Brain-derived neurotrophic factor improves proliferation of endometrial epithelial cells by inhibition of endoplasmic reticulum stress during early pregnancy
Brain-derived neurotrophic factor improves proliferation of endometrial epithelial cells by inhibition of endoplasmic reticulum stress during early pregnancy
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DOI：
10.1002/jcp.25834
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发表时间：
2017-12-01
影响因子：
5.6
通讯作者：
Song, Gwonhwa
中科院分区：
文献类型：
--
作者：
Lim, Whasun;Bae, Hyocheol;Song, Gwonhwa
脑源性神经营养因子（BDNF）是神经营养因子家族的成员，与两种跨膜受体结合：高亲和力的神经营养受体酪氨酸激酶2（NTRK 2）和低亲和力的p75。虽然中枢神经系统中的BDNF-NTRK 2信号是已知的，但女性生殖系统中的信号是未知的。因此，我们确定了BDNF对从妊娠第12天分离的猪子宫内膜腔上皮（pLE）细胞的影响，以及BDNF和NTRK 2在周期性和妊娠猪的子宫内膜中的表达。BDNF-NTRK 2基因在妊娠早期子宫腺上皮和子宫腔上皮表达。此外，它们在子宫GE和LE中的表达随着母猪胎次的增加而降低。重组BDNF可剂量依赖性地促进pLE细胞增殖，并促进pLE细胞核PCNA和Cyclin D1的表达。BDNF还可激活pLE细胞中AKT、P70 S6 K、S6、ERK 1/2、JNK、P38蛋白的磷酸化。此外，当用衣霉素和BDNF组合处理pLE细胞时，防止了由衣霉素诱导的ER应激引起的细胞死亡，这也减少了处于细胞周期的Sub-G（1）期的细胞。此外，衣霉素诱导的未折叠蛋白反应基因大多下调至基础水平相比，未经处理的pLE细胞。我们的研究结果表明，BDNF通过NTRK 2诱导pLE细胞的发育，通过PI 3 K和MAPK途径激活细胞信号传导，并通过抑制ER应激来维持着床和妊娠。
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family binds to two transmembrane receptors; neurotrophic receptor tyrosine kinase 2 (NTRK2) with high affinity and p75 with low affinity. Although BDNF-NTRK2 signaling in the central nervous system is known, signaling in the female reproductive system is unknown. Therefore, we determined effects of BDNF on porcine endometrial luminal epithelial (pLE) cells isolated from Day 12 of pregnancy, as well as expression of BDNF and NTRK2 in endometria of cyclic and pregnant pigs. BDNF-NTRK2 genes were expressed in uterine glandular (GE) and luminal (LE) epithelia during early pregnancy. In addition, their expression in uterine GE and LE decreased with increasing parity of sows. Recombinant BDNF increased proliferation in pLE cells in a dose-dependent, as well as expression of PCNA and Cyclin D1 in nuclei of pLE cells. BDNF also activated phosphorylation of AKT, P70S6K, S6, ERK1/2, JNK, P38 proteins in pLE cells. In addition, cell death resulting from tunicamycin-induced ER stress was prevented when pLE cells were treated with the combination of tunicamycin and BDNF which also decreased cells in the Sub-G(1) phase of the cell cycle. Furthermore, tunicamycin-induced unfolded protein response genes were mostly down-regulated to the basal levels as compared to non-treated pLE cells. Our finding suggests that BDNF acts via NTRK2 to induce development of pLE cells for maintenance of implantation and pregnancy by activating cell signaling via the PI3K and MAPK pathways and by inhibiting ER stress.