Brazilian Journal of Medical and Biological Research (2006) 39: 1373-1385 Blastocyst-endometrium interactions 1373 ISSN 0100-879X Review Blastocyst-endometrium interaction: intertwining a cytokine network W.A. Castro-Rendón1,2, 1Semillero de Investigación SIMBIOSIS, J.F. Castro-Álvarez1,2, 2Grupo Reproducción - Corporación Biogénesis, C. Guzmán-Martinez2 Universidad de Antioquia, Medellín, Colombia and J.C. Bueno-Sanchez1,2 Abstract Correspondence The successful implantation of the blastocyst depends on adequate Key words W.A. Castro-Rendón interactions between the embryo and the uterus. The development of • Embryo implantation Grupo Reproducción the embryo begins with the fertilized ovum, a single totipotent cell • Trophoblast Sede de Investigación Universitaria which undergoes mitosis and gives rise to a multicellular structure • Cytokines Cll 62 #52-59, Laboratorio 534 named blastocyst. At the same time, increasing concentrations of • Prostaglandins Universidad de Antioquia • Aspirin Medellín ovarian steroid hormones initiate a complex signaling cascade that Colombia stimulates the differentiation of endometrial stromal cells to decidual Fax: +57-4-210-6470 cells, preparing the uterus to lodge the embryo. Studies in humans and E-mail: [email protected] in other mammals have shown that cytokines and growth factors are produced by the pre-implantation embryo and cells of the reproduc- tive tract; however, the interactions between these factors that con- verge for successful implantation are not well understood. This review Received November 3, 2005 Accepted June 21, 2006 focuses on the actions of interleukin-1, leukemia inhibitory factor, epidermal growth factor, heparin-binding epidermal growth factor, and vascular endothelial growth factor, and on the network of their interactions leading to early embryo development, peri-implantatory endometrial changes, embryo implantation and trophoblast differen- tiation. We also propose therapeutical approaches based on current knowledge on cytokine interactions. Introduction stimulating factors (CSF), among others (1), supported by an adequate hormonal microen- Some decades ago cytokines were known vironment and the recognition of the fetus by as intercellular messengers with a unique the maternal immune system. The embryo function in the immune system. Subse- plays an active role in the modulation of the quently, experimental evidence showed that immunoendocrine activity during endome- they participate in many events of immu- trial implantation, particularly by participat- noendocrine interaction, characteristic of ing in (in the murine model) or enhancing (as complex signaling networks. Thus, the sig- in humans) the endometrial inflammatory nals from both the embryo and the mother reaction known as decidualization, thus regu- during early embryo development converge lating the production of maternal soluble around the actions of leukemia inhibitory factors that might be necessary for the inva- factor (LIF), interleukin-1 (IL-1) and colony- sion of the trophoblast for embryo lodging Braz J Med Biol Res 39(11) 2006 1374 W.A. Castro-Rendón et al. into the endometrium (2). These typical embryo begins when the oocyte is fertilized changes of decidualization can be induced by a spermatozoid. When the penetration of with oil, air bubbles or concanavalin A and the male gamete into the oocyte is con- have also been observed in deciduomata (3) cluded, maternal and paternal pronuclei mi- and ectopic pregnancies. grate to the center of the cell and the nuclear The decidual inflammatory reaction dif- membranes fuse to allow the recombination fers from the classical description of inflam- of the genetic material. This is the first stage mation that occurs in response to injury. In of embryo development, named zygote. Sub- particular, in decidua, the recruitment of sequently mitotic divisions of the zygote leukocytes is mainly dominated by natural give rise to the stages of two, four and eight killer (NK) cells that in other contexts are cells, until the morula (5). Then, the morula recognized as cytotoxic cells which partici- undergoes a process of cell polarization, pate in the antitumoral and antiviral immune where the outermost cells form the trophec- response. On the other hand, the transforma- toderm (external embryo layer). Simulta- tion of the uterine stromal cells into decidual neously, the expression and activation of cells is demonstrated by prolactin produc- Na+/K+ ATPase pumps transport sodium and tion, increased IL-15 concentrations and ac- water towards the interior of the morula that tivation of the arachidonic acid pathway. generates a cavity known as the blastocele These factors enhance the decidual reaction (6). Meanwhile, a group of pluripotent cells in response to embryo invasion. In general, denoted the inner cell mass is established in the decidual environment is able to regulate a pole of the embryo, between the trophecto- embryo differentiation, mainly the tropho- derm and the blastocele. These changes give ectodermic layer, which is dependent on rise to the blastocyst, the final step of early epithelial contact and extracellular matrix embryo development. proteins from the stroma in addition to cyto- Previous studies have provided informa- kines (4). These trophoectodermic/tropho- tion about the regulatory effects of the IL-1 blast cell subpopulations are producers of system in human pre-implantatory embryos, hormones and cytokines whose endocrine as well as in embryos of other species (Table action can cross the maternal-fetal interface 1). The IL-1 system is composed of two and directly influence the systemic physi- agonists (IL-1α and IL-1ß), one inhibitor ological changes that characterize gestation. designated IL-1 receptor antagonist (IL-l ra), In this intricate network of interactions and two receptors known as IL-1 receptors cytokines act as intermediary links of the type I (IL-1R tI) and type II. Interestingly, maternal-fetal relationship including the only IL-1R tI transduces a signal in response events related to decidualization, implanta- to IL-1 (7). Single blastomeres from human tion, placentation, embryogenesis, and fetal preimplantation embryos cultured in vitro growth. The aim of this review is to identify express the mRNAs for IL-1ß, IL-1R tI and certain basic aspects of cytokine actions in IL-1 ra (7). In bovine embryos the addition maternal-fetal interaction and to suggest new of IL-1ß after in vitro fertilization enhances possibilities for immunoendocrine regula- the recovery of blastocysts under conditions tion, which could be useful to understand of culture at high density (25-30 embryos/ some disorders of early pregnancy in hu- drop) but not at low density (10 embryos/ mans and in other animal species. drop). Thus, IL-1ß can modulate embryo development towards the blastocyst stage Early embryo development (8). Human embryos cultured in vitro pro- The establishment of the pre-implantatory duce high concentrations of IL-1α and IL- Braz J Med Biol Res 39(11) 2006 Blastocyst-endometrium interactions 1375 1ß (>60 and >80 pg/mL, respectively), and level at the stage of hatched blastocyst (10). the presence of these cytokines has been The aim of assisted reproductive tech- correlated with successful implantation after niques and embryo culture is to obtain em- transfer to the uterine cavity (9). Kruessel et bryos of good quality with the ability to al. (10) demonstrated the expression of IL- implant into the uterus. In this context, co- 1ß, IL-1R tI and IL-1 ra mRNA by RT-PCR culture systems of embryos on cell mono- in single-cell preimplantation mouse em- layers enhance early embryo development. bryos. They did not detect the corresponding Different types of cells such as uterine fibro- mRNAs at the stage of 2-cell-embryos, and blasts, human tubular cells, endometrial epi- only IL-1 ra was expressed at the 8-cell- thelial cells, and Vero cells (a cell line de- stage in a few embryos. Thus, the stage rived from green rhesus monkey kidney) where IL-1ß, IL-1R tI and IL-1 ra could be have been used successfully. These mono- detected was the compact morula stage. layers produce embryotrophic factors that Therefore, this expression was increased by make it possible to obtain a higher yield of ongoing maturation and reached its highest blastocysts. Some studies suggest that low Table 1. Cytokines, prostaglandins, and growth factors implicated in embryo-endometrium interaction. Compounds Biological actions Reference LIF Blastocyst implantation Stewart et al., 1992 (40) Early embryogenesis as an embryotrophin Lavranos et al., 1995 (16) Decidualization Chen et al., 2000 (41) LIFR Decidualization and placentation Ni et al., 2002 (31) IL-1 Successful implantation Sheth et al., 1991 (9) Induces LIF production Arici et al., 1995 (43) Induces COX-2 Huang et al., 1998 (26) Endometrial changes McMaster et al., 1992 (23) GM-CSF and CSF-1 production Garcia-Lloret et al., 1994 (57) IL-1 ra Failure of implantation Simon et al., 1994 (49) IL-1R tI Embryo development Kruessel et al., 1997 (10) EGF Blastocyst differentiation Kaye, 1997 (1) Angiogenic factor Moller et al., 2001 (37) Trophoblastic differentiation Kliman et al., 1990 (55) Induces LIF production Arici et al., 1995 (43) HB-EGF Blastocyst growth, zona-hatching and Das et al., 1994 (39) trophoblast outgrowth Leach et al., 1999 (36) Implantation reaction Wang et al., 1994 (46) IL-15 Decidual marker Okada et al., 2000 (19) IGFBP-1 Decidual marker Dimitriadis et al., 2002 (20) TNF-α Endometrial changes von