Irwin J C, de las Fuentes L, Giudice L C
Department of Gynecology and Obstetrics, Stanford University Medical Center, California 94305.
Ann N Y Acad Sci. 1994 Sep 30;734:7-18. doi: 10.1111/j.1749-6632.1994.tb21730.x.
Growth factors are believed to act as local regulators of endometrial cyclic activity, but there is limited information on their regulation of decidual differentiation and function. Cell cultures of human endometrial stroma treated with progesterone (P) undergo morphologic, proliferative and secretory changes characteristic of decidualizing endometrium. In the presence of P, different growth factors can stimulate cell proliferation, but decidual differentiation is induced specifically by EGF, as shown by the production of prolactin (PRL), fibronectin, laminin, and insulin-like growth factor binding protein 1 (IGFBP-1). The present study investigates the effects of the insulin-like growth factors (IGF-I, IGF-II) on decidualization in vitro, as indicated by a P-dependent growth response and by the secretion of PRL and IGFBP-1. IGFs were required together with EGF and P to stimulate stromal cell proliferation. In contrast, PRL (38 +/- 4 ng/day/10(6) cells) and IGFBP-1 (26 +/- 3 micrograms/day/10(6) cells) were secreted by in vitro decidualized cells in the absence of exogenous IGFs. However, IGFs regulated both IGFBP-1 and PRL secretion in a dose-dependent biphasic manner. Stimulation of IGFBP-1 (200-250%) and PRL (243-324%) peaked at 1 ng/ml for IGF-I, and 10 ng/ml for IGF-II, followed by inhibition at higher peptide concentrations (ED50s 3 and 30 ng/ml, respectively). Maximal physiological doses (100 ng/ml) of IGF-I and IGF-II virtually abolished IGFBP-1 secretion (1% and 2% of basal levels, respectively), but did not cause total suppression of PRL secretion (8% and 22% of basal levels). IGF-induced mitogenesis was inversely correlated with endogenous IGFBP-1 levels in in vitro decidualized stromal cultures. Our studies show that growth factor interactions regulate decidual function, and that specific cellular functions associated with the decidual response are differentially regulated by growth factor interactions. Our findings support a role for the IGF system in autocrine/paracrine interactions during decidualization and early pregnancy. It is speculated that IGF-II may constitute one of the embryonic signaling mechanisms during early postimplantation stages.
生长因子被认为是子宫内膜周期性活动的局部调节因子，但关于它们对蜕膜分化和功能的调节作用，目前的信息有限。用孕酮（P）处理的人子宫内膜基质细胞培养物会经历蜕膜化子宫内膜特有的形态、增殖和分泌变化。在有P存在的情况下，不同的生长因子可刺激细胞增殖，但蜕膜分化是由表皮生长因子（EGF）特异性诱导的，这可通过催乳素（PRL）、纤连蛋白、层粘连蛋白和胰岛素样生长因子结合蛋白1（IGFBP-1）的产生来证明。本研究调查了胰岛素样生长因子（IGF-I、IGF-II）对体外蜕膜化的影响，这可通过P依赖的生长反应以及PRL和IGFBP-1的分泌来体现。IGF需要与EGF和P共同作用以刺激基质细胞增殖。相比之下，在没有外源性IGF的情况下，体外蜕膜化细胞会分泌PRL（38±4 ng/天/10⁶细胞）和IGFBP-1（26±3 μg/天/10⁶细胞）。然而，IGF以剂量依赖的双相方式调节IGFBP-1和PRL的分泌。IGF-I在1 ng/ml时，IGFBP-1（200 - 250%）和PRL（243 - 324%）的刺激作用达到峰值；IGF-II在10 ng/ml时达到峰值，随后在更高的肽浓度下受到抑制（ED50分别为3和30 ng/ml）。IGF-I和IGF-II的最大生理剂量（100 ng/ml）实际上使IGFBP-1分泌几乎完全消失（分别为基础水平的1%和2%），但并未导致PRL分泌完全受抑制（分别为基础水平的8%和22%）。在体外蜕膜化的基质培养物中，IGF诱导的有丝分裂与内源性IGFBP-1水平呈负相关。我们的研究表明，生长因子相互作用调节蜕膜功能，并且与蜕膜反应相关的特定细胞功能受到生长因子相互作用的差异调节。我们的研究结果支持IGF系统在蜕膜化和早期妊娠期间的自分泌/旁分泌相互作用中发挥作用。据推测，IGF-II可能构成植入后早期阶段的一种胚胎信号传导机制。
