Pleiotropy and redundancy of STAT proteins in early pregnancy.
ABSTRACT Signal transducers and activators of transcription (STATs) are a group of proteins involved in signal transduction from numerous bioactive substances. Hormones and cytokines such as leukaemia inhibitory factor, interferon-tau and prolactin, which play key roles during early pregnancy, activate the Janus kinase (JAK)/STAT signalling pathway. The STATs are thus involved in the regulation of implantation, establishing uterine receptivity and regulation of the maternal immune response. It seems that STATs can orchestrate signals from hormones and cytokines in different cell types and may therefore generate numerous biological effects, despite the relatively small number of receptors activating the JAK/STAT pathway. This review summarizes the participation of STATs in the main processes of early pregnancy, especially regarding their pleiotropy and redundancy.
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ABSTRACT: All cardinal events during the reproductive cycle, including ovulation, implantation, and menstruation, are characterized by a profound tissue remodeling and an associated local inflammatory response. The ovarian hormone progesterone is a key modulator of inflammatory signals in reproductive tissues, but the underlying mechanisms are not well understood. In this study, we report that differentiating human endometrial stromal cells (ESCs) acquire resistance to interferon-gamma (IFNgamma)-dependent signal transducers and activators of transcription (STAT) 1 signaling, although phosphorylation, nuclear translocation, and binding of STAT1 to DNA, are unaffected. These observations prompted an investigation into the role of nuclear repressors of STAT1 signaling. We demonstrate that protein inhibitor of activated STAT-y is complexed to the progesterone receptor (PR) in human ESCs and that its ability to repress STAT1 signaling is dependent upon activation of PR in response to hormone binding. Conversely, IFNgamma and protein inhibitor of activated STAT-y synergistically inhibited PR-dependent transcription, demonstrating that the progesterone and IFNgamma signaling pathways engage in reciprocal transcriptional antagonism in human endometrium.Molecular Endocrinology 09/2004; 18(8):1988-99. · 4.75 Impact Factor
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ABSTRACT: In humans, functional deficiency of alpha-2M is not known, implying alpha 2M is essential for gestational success. Mice, deficient in two members of the alpha-2 Macroglobulin (alpha 2M) family, i.e. alpha-2 macroglobulin (MAM) and murinoglobulin-1 (MUG-1) are viable, fertile and phenotypically normal, unless stressed (Am J Pathol, 155 (1999), 983). Here, we analysed implantation sites in MAM(-/-)/MUG-1(-/-)mice during pregnancy, a strong physiological stressor. Despite some post-implantation fetal loss, mean litter size was comparable to congenic C57Bl/6J (B6) mice, but MAM(-/-)/MUG-1(-/-)pups were significantly lighter and the sex ratio was skewed towards males. Implantation sites appeared histologically normal up to gestational day (gd) 8. By gd 10, extensive over-development of trophoblasts was evident, accompanied by relative deficits in decidua, in the mural mesometrial lymphoid aggregates of pregnancy and in uterine Natural Killer cells. At gd 10-12, decidual spiral arteries were dilated but abnormally cuffed by trophoblasts that extended anomalously, for midgestation, to the myometrial circular smooth muscle. Ultrastructurally, trophoblasts in the mesometrial decidua made intimate contact with endothelial cells that were shedding membrane fragments. These findings demonstrate that alpha 2M, and thereby proteinases and/or cytokines whose bio-availability is regulated by alpha 2M, exert significant decidual regulation on trophoblast invasion.Placenta 12/2003; 24(10):912-21. · 3.12 Impact Factor
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ABSTRACT: Animal models and experimental studies suggest a role for paracrine prolactin (PRL) signalling in decidualization and embryo implantation. We investigated the expression of endometrial prolactin (e-PRL) and prolactin receptor (PRL-R) in the endometrium of women affected by unexplained infertility (UI) and repeated miscarriages (RM). Patients (n = 24) were divided into three groups: RM, n = 5; UI, n = 11; controls, n = 8. Endometrial samples were collected at the time of hysteroscopy in the late luteal phase. The presence of transcripts of e-PRL and PRL-R was investigated by qualitative RT-PCR. Pattern and site of expression of e-PRL were studied by immunohistochemistry. PRL-R mRNA was detected in all endometrial samples of the three groups. PRL gene expression was detected in all control samples, only in three of five samples of the RM group and in four of 11 samples of the UI group. RT-PCR results were largely confirmed by immunohistochemistry, study groups showing a defect of expression of e-PRL. In this pilot study we report a lack of expression of endometrial prolactin during the 'implantation window' in some patients affected by unexplained infertility and repeated miscarriages. These data, in association with those obtained in experimental animals, suggest that the lack of endometrial PRL expression is involved in reproduction failure.Human Reproduction 09/2004; 19(8):1911-6. · 4.67 Impact Factor