Embryo implantation is a crucial step for successful pregnancy. Prior to implantation, the luminal epithelium undergoes steroid hormone-induced structural and functional changes that render it competent for embryo attachment. Subsequent invasion of the embryo into the maternal tissue triggers differentiation of the underlying stromal cells to form the decidua, a transient tissue which supports the developing embryo. Many molecular cues of both stromal and epithelial origin have been identified that are critical mediators of this process. An important aspect of uterine biology is the elaborate crosstalk that occurs between these tissue compartments during early pregnancy through expression of paracrine factors regulated by the steroid hormones estrogen and progesterone. Aberrant expression of these factors often leads to implantation failure and infertility. Genetically-engineered mouse models have been instrumental in elucidating what these paracrine factors are, what drives their expression, and what their effects are on neighboring cells. This review provides an overview of several well-characterized signaling pathways that span both epithelial and stromal compartments and their function during implantation in the mouse.

Progesterone, acting through the progesterone receptors (PGRs), is one of the most critical regulators of endometrial differentiation, known as decidualization, which is a key step toward the establishment of pregnancy. Yet a long-standing unresolved issue in uterine biology is the precise roles played by the major PGR isoforms, PGR-A and PGR-B, during decidualization in the human. Our approach, expressing PGR-A and PGR-B individually after silencing endogenous PGRs in human endometrial stromal cells (HESCs), enabled the analysis of the roles of these isoforms separately as well as jointly. Chromatin immunoprecipitation-sequencing in combination with gene expression profiling revealed that PGR-B controls a substantially larger cistrome and transcriptome than PGR-A during HESC differentiation. Interestingly, PGR-B directly regulates the expression of PGR-A. De novo motif analysis indicated that, although the 2 isoforms bind to the same DNA sequence motif, there are both common and unique neighboring motifs where other transcription factors, such as FOSL1/2, JUN, C/EBPβ, and STAT3, bind and dictate the transcriptional activities of these isoforms. We found that PGR-A and PGR-B regulate overlapping as well as distinct sets of genes, many of which are known to be critical for decidualization and establishment of pregnancy. When PGR-A and PGR-B were coexpressed during HESC differentiation, PGR-B played a predominant role, although both isoforms influenced each other's transcriptional activity. This study revealed the gene networks that operate downstream of each PGR isoform to mediate critical functions, such as regulation of the cell cycle, angiogenesis, lysosomal activation, insulin receptor signaling, and apoptosis, during decidualization in the human.

Implantation is an essential process during establishment of pregnancy in mammals. It is initiated with the attachment of the blastocyst to a receptive uterine epithelium followed by its invasion into the stromal tissue. These events are profoundly regulated by the steroid hormones 17β-estradiol and progesterone. During the past several years, mouse models harboring conditional gene knockout mutations have become powerful tools for determining the functional roles of cellular factors involved in various aspects of implantation biology. Studies using these genetic models as well as primary cultures of human endometrial cells have established that the estrogen receptor α, the progesterone receptor, and their downstream target genes critically regulate uterine growth and differentiation, which in turn control embryo-endometrial interactions during early pregnancy. These studies have uncovered a diverse array of molecular cues, which are produced under the influence of estrogen receptor α and progesterone receptor and exchanged between the epithelial and stromal compartments of the uterus during the progressive phases of implantation. These paracrine signals are critical for acquisition of uterine receptivity and functional interactions with the embryo. This review highlights recent work describing paracrine mechanisms that govern steroid-regulated uterine epithelial-stromal dialogue during implantation and their roles in fertility and disease.

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Aqueous extracts of ginseng polysaccharides have been shown to modulate the immune response by inducing cytokine and nitric oxide (NO) production, however, the exact mechanism(s) of action remains unclear. The aim of the current study was to determine the effect of ginseng polysaccharides (PS) on MAPK and NF‐κB pathways, known mediators of the immune response, using murine macrophage cells (RAW 264.7). Cells were treated with or without PS for 0–60 minutes, harvested at 15 minute increments, and cellular proteins were analyzed for phosphorylated levels of I κB, ERK, JNK, and p38. Time‐dependent increases in phospho‐IκB, phospho‐ERK, and phospho‐JNK were observed in PS treated cells. Further analysis of nuclear extracts by EMSA showed enhanced NF‐κB activity following 24 hours of PS treatment. Cells were then pre‐treated with specific inhibitors of ERK (PD98059), p38 (SB202190), JNK (SP60012), and NF‐κB (PDTC), followed by PS, and supernatants were assessed for NO and tumor necrosis factor‐alpha (TNFα) production. Nitric oxide levels were robustly increased in PS treated cells, and this effect was partially blocked by PD98059 and PDTC. TNFα secretion was also stimulated by PS treatment, however only PDTC was able to attenuate the PS response. These results show that both MAPK and NF‐κB pathways are involved in PS‐induced nitric oxide production, while the effects on TNFα release appear to be mediated by NF‐κB only.