The primary function of the corpus luteum is secretion of the hormone progesterone, which is required for maintenance of normal pregnancy in mammals. The corpus luteum develops from residual follic...

https://www.physiology.org/doi/pdf/10.1152/physrev.2000.80.1.1

Mechanisms Controlling the Function and Life Span of the Corpus Luteum

Successful implantation is the result of reciprocal interactions between the implantation-competent blastocyst and receptive uterus. Although various cellular aspects and molecular pathways of this dialogue have been identified, a comprehensive understanding of the implantation process is still missing. The receptive state of the uterus, which lasts for a limited period, is defined as the time when the uterine environment is conducive to blastocyst acceptance and implantation. A better understanding of the molecular signals that regulate uterine receptivity and implantation competency of the blastocyst is of clinical relevance because unraveling the nature of these signals may lead to strategies to correct implantation failure and improve pregnancy rates. Gene expression studies and genetically engineered mouse models have provided valuable clues to the implantation process with respect to specific growth factors, cytokines, lipid mediators, adhesion molecules, and transcription factors. However, a staggering amount of information from microarray experiments is also being generated at a rapid pace. If properly annotated and explored, this information will expand our knowledge regarding yet-to-be-identified unique, complementary, and/or redundant molecular pathways in implantation. It is hoped that the forthcoming information will generate new ideas and concepts for a process that is essential for maintaining procreation and solving major reproductive health issues in women.

Molecular cues to implantation

Transglutaminases (Tgases) are a widely distributed group of enzymes that catalyse the post-translational modification of proteins by the formation of isopeptide bonds. This occurs either through protein cross-linking via epsilon-(gamma-glutamyl)lysine bonds or through incorporation of primary amines at selected peptide-bound glutamine residues. The cross-linked products, often of high molecular mass, are highly resistant to mechanical challenge and proteolytic degradation, and their accumulation is found in a number of tissues and processes where such properties are important, including skin, hair, blood clotting and wound healing. However, deregulation of enzyme activity generally associated with major disruptions in cellular homoeostatic mechanisms has resulted in these enzymes contributing to a number of human diseases, including chronic neurodegeneration, neoplastic diseases, autoimmune diseases, diseases involving progressive tissue fibrosis and diseases related to the epidermis of the skin. In the present review we detail the structural and regulatory features important in mammalian Tgases, with particular focus on the ubiquitous type 2 tissue enzyme. Physiological roles and substrates are discussed with a view to increasing and understanding the pathogenesis of the diseases associated with transglutaminases. Moreover the ability of these enzymes to modify proteins and act as biological glues has not gone unnoticed by the commercial sector. As a consequence, we have included some of the present and future biotechnological applications of this increasingly important group of enzymes.

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Transglutaminases: Nature’s biological glues

Leukemia inhibitory factor is essential for embryo implantation, and a shift from type 1 T-helper to type 2 T-helper response at the fetal-maternal interface may contribute to successful pregnancy. We show that LIF production is associated with type 2 T-helper cells, is upregulated by IL-4 and progesterone and is downregulated by IL-12, IFN-gamma and IFN-alpha. We also show a decreased production of LIF, IL-4 and IL-10 by decidual T cells of women with unexplained recurrent abortions in comparison with that of women with normal gestation. The defective production of LIF and/or type 2 T-helper cytokines may contribute to the development of unexplained recurrent abortions.

Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions.

The ovary and uterus undergo extensive tissue remodeling throughout each reproductive cycle. This remodeling of the extracellular environment is dependent upon the cyclic hormonal changes associated with each estrous or menstrual cycle. In the ovary, tissue remodeling is requisite for growth and expansion of the follicle, breakdown of the follicular wall during the ovulatory process, transformation of the postovulatory follicle into the corpus luteum, as well as the structural dissolution of the corpus luteum during luteal regression. In the uterus, there is extraordinary turnover of the endometrial connective tissue matrix during each menstrual cycle. This turnover encompasses the complete breakdown and loss of this layer, followed by its subsequent regrowth. With implantation, extensive remodeling of the uterus occurs to support placentation. These dynamic changes in the ovarian and uterine extracellular architecture are regulated, in part, by the matrix metalloproteinase (MMP) system. The MMP system acts to control connective tissue remodeling processes throughout the body and is comprised of both a proteolytic component, the MMPs, and a regulatory component, the associated tissue inhibitors of metalloproteinases. The current review will highlight the key features of the MMPs and tissue inhibitors of metalloproteinases, focus on the changes and regulation of the MMP system that take place throughout the estrous and menstrual cycles, and address the impact of the dynamic tissue remodeling processes on ovarian and uterine physiology.

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The Matrix Metalloproteinase System: Changes, Regulation, and Impact throughout the Ovarian and Uterine Reproductive Cycle

Leukemia inhibitory factor (LIF), a cytokine that induces macrophage differentiation in the murine Ml myeloid leukemia cellline, is essential for blastocyst implantation in mice However, its expression and the role it plays in the human uterus areunknown To clarify these issues, we examined LIF gene expression in the human uterus by Northern blot hybridization and bya quantitative reverse transcription-polymerase chain reaction (RT-PCR) method Analysis of LIF mRNA showed two hybridizationbands, with estimated mRNA sizes of about 40-kb pairs and 18-kb pairs LIF mRNA was detected at high levels in endometrialtissue and decidua, but at low levels in the chorionic villus in first trimester and term placenta In the secretory phase, theendometrial tissue showed higher LIF expression than in the proliferative phase (95-fold; p < 001) The endometrial tissueswere separated into a stroma-enriched fraction (SF) and an epithelium-enriched fraction (EF), and the LIF mRNA levels in eachfraction were examined by quantitative RT-PCR These levels were higher in the EF than in the SF (33-fold; p < 005) Thesefindings suggest that, in humans, LIF plays a role in uterine function during the menstrual cycle, as well as during pregnancy

Expression of leukemia inhibitory factor in human endometrium and placenta.

Endometrial stromal differentiation (decidualization) is essential for implantation of the developing blastocyst. To investigate the process of progesterone (P)-induced decidualization of human endometrial stromal cells (ESC), a complementary DNA library enriched with P-induced genes was constructed from cultured human ESC by subtractive hybridization and the polymerase chain reaction. One of the isolated clones was the complementary DNA for the tissue inhibitor of metalloproteinase-3 (TIMP-3), a recently identified member of the human TIMP family. When human ESC were cultured in the presence of P for 6 days, the induction of TIMP-3 messenger RNA (mRNA) expression was observed by Northern blotting. In contrast, the marked induction of PRL mRNA expression and morphological changes were observed after 9 days of culture. P-induced TIMP-3 mRNA expression was dose dependent, and this induction was inhibited by the antiprogestin RU486. Estrogen did not induce TIMP-3 mRNA expression under similar conditions. In ...

Induction of tissue inhibitor of metalloproteinase 3 gene expression during in vitro decidualization of human endometrial stromal cells

Leukaemia inhibitory factor (LIF) is a cytokine that displays multiple activities in various tissues and is essential for blastocyst implantation in mice. In the human uterus, LIF is expressed in endometrial tissue and the decidua. To elucidate the role it plays, the mRNA levels for two LIF receptor (R) subunits, LIF-R and gp130, were examined in human endometrium, placenta and decidua by Northern blot hybridization. The expression of LIF-R gene was detected in the chorionic villus during the first trimester, in term placenta, and at lower levels in the decidua. The expression of LIF-R gene was not detectable in non-pregnant endometrium. The expression of the gp130 gene was detected in all tissues examined. During pregnancy, there was no significant change in the mRNA concentration of LIF-R in the placenta, while that of gp130 increased after the second trimester. The human choriocarcinoma cell line, BeWo, was found to express LIF-R and gp130. LIF inhibited forskolin-induced human chorionic gonadotrophin (HCG)-beta production by BeWo in a dose-dependent manner, and it ameliorated forskolin-induced growth suppression. These findings suggest that LIF plays a regulatory role in trophoblast growth and differentiation during pregnancy in human placenta.

Molecular interactions during pregnancy: Expression of leukaemia inhibitory factor (LIF) receptor in human placenta: a possible role for LIF in the growth and differentiation of trophoblasts

Expression of leukaemia inhibitory factor (LIF) receptor in human placenta: a possible role for LIF in the growth and differentiation of trophoblasts

Increasing evidence suggests that macrophage colony-stimulating factor (M-CSF) is produced in the uterine endometrium and that it plays an important role in the reproductive process. In the present study, using an in vitro decidualization model and human endometrium, we investigated M-CSF messenger RNA (mRNA) expression in human endometrial stromal cells (ESC) by Northern blotting and in situ hybridization. The secreted M-CSF in the culture medium of ESC was measured by enzyme-linked immunosorbent assay. ESC were cultured in the presence of progesterone (P) or estrogen. After a 9-day culture with P, when in vitro decidualization was confirmed by the production of PRL, M-CSF mRNA and protein levels were 3.1 +/- 0.5- and 3.2 +/- 0.8-fold (mean +/- SEM) higher, respectively, than those in cultures without P (P < 0.01). The P-induced increase was dose dependent. On the other hand, estrogen did not increase M-CSF mRNA expression. M-CSF mRNA expression in the first trimester deciduae that expressed PRL mRNA was...

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Mariko Fujimoto

Papers

Expression of leukemia inhibitory factor in human endometrium and placenta.

Induction of tissue inhibitor of metalloproteinase 3 gene expression during in vitro decidualization of human endometrial stromal cells

Molecular interactions during pregnancy: Expression of leukaemia inhibitory factor (LIF) receptor in human placenta: a possible role for LIF in the growth and differentiation of trophoblasts

Expression of leukaemia inhibitory factor (LIF) receptor in human placenta: a possible role for LIF in the growth and differentiation of trophoblasts

Progesterone enhances macrophage colony-stimulating factor production in human endometrial stromal cells in vitro.