Jasinska Anna, Strakova Zuzana, Szmidt Maciej, Fazleabas Asgerally T
Department of Obstetrics and Gynecology, University of Illinois, 820 South Wood Street, M/C 808, Chicago, Illinois 60612-7313, USA.
Endocrinology. 2006 Sep;147(9):4112-21. doi: 10.1210/en.2005-1577. Epub 2006 Jun 1.
Endometrial apoptosis increases from the proliferative phase through the secretory phase and peaks at menses. However, with the onset of pregnancy, the corpus luteum is rescued and stromal cells, instead of undergoing apoptosis, reorganize the cytoskeleton and then begin to differentiate. We hypothesized that in the presence of hormones (estradiol-17beta and medroxyprogesterone acetate), chorionic gonadotropin (hCG) as an early embryonic signal, and induction of decidualization by dibutyryl-cAMP (dbcAMP), endometrial stromal cells are rescued by the regulation of proteins that inhibit apoptosis. The percentage of cells stained with annexin V, an early apoptotic marker, increased dramatically after cytoskeletal disruption with cytochalasin D compared with non-cytochalasin-D-treated controls (P < 0.05). However, treatment of cells with hCG or dbcAMP in the presence of hormones significantly (P < 0.05) decreased the percentage of annexin-V-stained cells compared with cells treated with cytochalasin D alone. This inhibition was further confirmed by immunodetection of cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The inhibition of apoptosis by hCG and dbcAMP was via the intrinsic pathway because the cytochalasin-D-treated cells stained intensely for Bax, whereas the cells treated with hormones, hCG, or dbcAMP stained predominantly for Bcl-2. Treatment of cytochalasin-D-treated cells with hormones and dbcAMP resulted in an increase in the secretion of IGF-binding protein-1 (IGFBP-1) and prolactin. Treatment of cytochalasin-D-treated cells with recombinant IGFBP-1 and prolactin also inhibited apoptosis. These data suggest that under in vitro conditions, both hCG and the induction of decidualization play a direct role in preventing uterine stromal cells from undergoing apoptosis. Furthermore, this inhibition of apoptosis may be mediated in part by IGFBP-1 and prolactin and the alteration in the expression of Bcl-2 and Bax.
子宫内膜凋亡从增殖期到分泌期逐渐增加，并在月经期达到峰值。然而，随着妊娠的开始，黄体得以挽救，基质细胞不再发生凋亡，而是重新组织细胞骨架，然后开始分化。我们推测，在激素（雌二醇 - 17β和醋酸甲羟孕酮）、作为早期胚胎信号的绒毛膜促性腺激素（hCG）以及二丁酰 - cAMP（dbcAMP）诱导蜕膜化的存在下，子宫内膜基质细胞通过抑制凋亡的蛋白质调节而得以挽救。与未用细胞松弛素D处理的对照组相比，用细胞松弛素D破坏细胞骨架后，早期凋亡标志物膜联蛋白V染色的细胞百分比显著增加（P < 0.05）。然而，在激素存在的情况下，用hCG或dbcAMP处理细胞，与仅用细胞松弛素D处理的细胞相比，膜联蛋白V染色细胞的百分比显著降低（P < 0.05）。通过检测裂解的半胱天冬酶 - 3和末端脱氧核苷酸转移酶dUTP缺口末端标记染色进一步证实了这种抑制作用。hCG和dbcAMP对凋亡的抑制作用是通过内在途径实现的，因为用细胞松弛素D处理的细胞Bax染色强烈，而用激素、hCG或dbcAMP处理的细胞主要染为Bcl - 2。用激素和dbcAMP处理细胞松弛素D处理的细胞导致胰岛素样生长因子结合蛋白 - 1（IGFBP - 1）和催乳素分泌增加。用重组IGFBP - 1和催乳素处理细胞松弛素D处理的细胞也抑制了凋亡。这些数据表明，在体外条件下，hCG和蜕膜化诱导在防止子宫基质细胞凋亡中都起直接作用。此外，这种对凋亡的抑制可能部分由IGFBP - 1和催乳素以及Bcl - 2和Bax表达的改变介导。
