Academic literature on the topic 'Cytokines; pre-implantation embryo; inflammation'

The cytokine milieu surrounding the pre-implantation embryo contributes to programming optimal embryo development. Perturbations to the maternal environment such as infection and inflammation during the pre-implantation period can influence cytokine synthesis and may cause changes in embryo development that compromise pregnancy outcome. We aimed to investigate the effect of an inflammatory insult with LPS during the pre-implantation period on later fetal development and the role of oviduct cytokine expression in mediating this response. LPS (at various doses of 0.5–62.5 μg) was administered i.p. to C57Bl/6 mice on both day 3 and day 4 post coitum (pc). The effects of treatment on day 4 blastocysts and day 18 fetal development were analysed. Blastocysts from LPS-treated mothers showed reduced viability and smaller total cell number, but were only significant when doses of >12.5 μg LPS were administered. This was not a direct effect of LPS, as no effect of LPS on embryo development in vitro was seen, even at very high LPS concentrations (25 μg/mL). At day 18 pc, pregnancy rates and the number of viable fetuses, as well as fetal and placenta weights were all reduced after low dose LPS treatment (0.5 μg) compared to control PBS-treated females. qPCR analysis of day 4 oviduct tissue revealed that administration of 12.5ug of LPS resulted in increased mRNA expression of cytokines including IL6, TNFA, IL1B, IFNG, IL10 and LIF. Our findings show that a modest pro-inflammatory insult with LPS in the pre-implantation period programs the embryo for later adverse effects on fetal and placental development. The effects of LPS appear to be mediated indirectly via the maternal tract, and altered oviduct cytokine expression which impairs pre-implantation embryo development is implicated as the underlying mechanism. This model will now be utilised to investigate the potential role of specific inflammatory cytokines TNFA and IFNG in mediating this response.

Implantation failure, which is presently the major barrier in human fertility, is attributed, in many cases, to the failure of the uterus to acquire receptivity. The transition into a receptive uterus includes cellular changes in the endometrium and the modulated expression of different cytokines, growth factors, transcription factors, and prostaglandins. These molecules partake in the generation of an inflammatory response followed by the recruitment of immune cells. These cells have shown to be involved in the maternal immune tolerance toward the implanted embryo as well as in the maternal–fetus interaction during pregnancy. Most of the accumulated evidence indicates that embryo implantation is associated with an active Th1 inflammatory response while a Th2-humoral inflammation is required for pregnancy maintenance. Yet, recent findings suggest that a Th1 inflammatory response is also necessary for the acquisition of uterine receptivity. This notion was originally suggested by reports from our and other clinical centers worldwide that IVF patients with repeated implantation failure subjected to endometrial biopsy exhibit a substantial improvement in their chances to conceive. These findings, followed by the demonstration of an elevated pro-inflammatory cytokine/chemokine expression, as well as an increased abundance of immune cells, in the endometrium of these patients, raised the idea that acquisition of uterine receptivity is closely associated with an inflammatory response. This review summarizes the molecular and biochemical evidence that confirm this notion and proposes a mechanism by which injury-induced inflammation improves uterine receptivity and the subsequent pregnancy outcome.

In the United States, 36.5% of women between the ages of 20 and 39 years are obese. This obesity results in not only metabolic disorders including type II diabetes and cardiovascular disease, but also impaired female fertility. Systemic and tissue-specific chronic inflammation and oxidative stress are common characteristics of obesity. This is also true in the ovary. Several studies have demonstrated that pro-inflammatory cytokines and reactive oxygen species alter estrous cyclicity, steroidogenesis and ovulation. Inflammation and oxidative stress also impair meiotic and cytoplasmic maturation of the oocyte which reduces its developmental competence for fertilization and pre-implantation embryo development. Interestingly, there is recent evidence that obesity- and/or polycystic ovary syndrome (PCOS)-dependent changes to the gut microbiome contributes to ovarian inflammation, steroidogenesis and the expression of mRNAs in the oocyte. However, several gaps remain necessitating future studies to identify inflammation, oxidative stress and gut microbiome mechanisms that reduce ovarian function and oocyte quality.

During pregnancy, the mother’s immune system has to tolerate the persistence of paternal alloantigens without affecting the anti-infectious immune response. Consequently, several mechanisms aimed at preventing allograft rejection, occur during a pregnancy. In fact, the early stages of pregnancy are characterized by the correct balance between inflammation and immune tolerance, in which proinflammatory cytokines contribute to both the remodeling of tissues and to neo-angiogenesis, thus, favoring the correct embryo implantation. In addition to the creation of a microenvironment able to support both immunological privilege and angiogenesis, the trophoblast invades normal tissues by sharing the same behavior of invasive tumors. Next, the activation of an immunosuppressive phase, characterized by an increase in the number of regulatory T (Treg) cells prevents excessive inflammation and avoids fetal immuno-mediated rejection. When these changes do not occur or occur incompletely, early pregnancy failure follows. All these events are characterized by an increase in different growth factors and cytokines, among which one of the most important is the angiogenic growth factor, namely placental growth factor (PlGF). PlGF is initially isolated from the human placenta. It is upregulated during both pregnancy and inflammation. In this review, we summarize current knowledge on the immunomodulatory effects of PlGF during pregnancy, warranting that both innate and adaptive immune cells properly support the early events of implantation and placental development. Furthermore, we highlight how an alteration of the immune response, associated with PlGF imbalance, can induce a hypertensive state and lead to the pre-eclampsia (PE).

Abstract: The aim of this review is to explore, in addition to revealing the biological background, new conceptual and therapeutic approaches for reproductive clinicians to provide better and more effective care for sterile and infertile couples. In humans, 75% of unsuccessful pregnancies are the result of failures of implantation, and implantation failure is the limiting factor for in vitro fertilization treatment. A modified “good” inflammation is necessary for implantation and parturition, but for most of pregnancy, inflammation threatens the continuation of pregnancy. During this period, maintaining the non-inflammatory condition is extremely important, enabling the maternal epigenetic effects to occur in the fetus, making it possible for the offspring to adapt as much as possible to the extrauterine life. In the maintenance of the non-inflammatory condition of pregnancy, a large amount of progesterone hormone produced by the placenta (after the luteo-placental shift) plays a crucial role. It has been reported that the role of inflammation during implantation is an ancestral response to the embryo as a foreign body. During normal pregnancy, this inflammation is initiated by the trophoblast and involves the suppression of neutrophil infiltration, the recruitment of natural killer cells to the site of implantation as well as the production of a range of proinflammatory cytokines. During the “implantation window”, the uterus is primed to produce several inflammatory signals such as prostaglandin E2 and a range of proinflammatory cytokines, including TNF, IL6 and IFNγ. The feto-placental unit is a semi-foreign graft called a “semi allograft”, and the recognition of pregnancy by the mother (host) and the resulting maternal immune tolerance is an essential part of successful pregnancy and the birth of a healthy fetus. Because of the functional or absolute reduction of circulating progesterone (due to the decreasing hormone production of the physiologically “aging” placenta after around the 36th week of pregnancy) progesterone effects become insufficient. Therefore it is unable to suppress the production of IL8 and other inflammatory cytokines and the term inflammation, leading to cervical ripening, uterus contractions and parturition (“good” inflammation). Orv Hetil. 2019; 160(32): 1247–1259.

Ureaplasma diversum is an opportunistic pathogen associated with uterine inflammation, impaired embryo implantation, infertility, abortions, premature birth of calves and neonatal pneumonia in cattle. It has been suggested that the intra-uterine infection by Ureaplasma diversum can cause vascular changes that hinder the success of pregnancy. Thus, the aim of this study was to evaluate the changes of intrauterine site of A/J mice in estrus or proestrus phase inoculated with Ureaplasma diversum. The infection was monitored at 24, 48 and 72 hours by the PCR methodology to detect the Ureaplasma in the inoculation site and the profile of circulating blood cells. Morphological changes, intensity of inflammation and the production of cytokines were compared. The infected mice showed local inflammation through the production of IFN-γ and TNF-α. Ureaplasma diversum infections in the reproductive tract of studied mice seemed to be associated with the production of pro-inflammatory cytokines in uterine parenchyma. The levels of TNF-α of infected mice were dependent on the bacterial load of inoculated Ureaplasma. Uterine experimental infections by Ureaplasma diversum have not been mentioned yet and herein we presented the first report of an intrauterine infection model in mice.

Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII; NR2F2) is an orphan nuclear receptor involved in cell-fate specification, organogenesis, angiogenesis, and metabolism. Ablation of COUP-TFII in the mouse uterus causes infertility due to defects in embryo attachment and impaired uterine stromal cell decidualization. Although the function of COUP-TFII in uterine decidualization has been described in mice, its role in the human uterus remains unknown. We observed that, as in mice, COUP-TFII is robustly expressed in the endometrial stroma of healthy women, and its expression is reduced in the ectopic lesions of women with endometriosis. To interrogate the role of COUP-TFII in human endometrial function, we used a small interfering RNA-mediated loss of function approach in primary human endometrial stromal cells. Attenuation of COUP-TFII expression did not completely block decidualization; rather it had a selective effect on gene expression. To better elucidate the role of COUP-TFII in endometrial stroma cell biology, the COUP-TFII transcriptome was defined by pairing microarray comparison with chromatin immunoprecipitation followed by deep sequencing. Gene ontology analysis demonstrates that COUP-TFII regulates a subset of genes in endometrial stroma cell decidualization such as those involved in cell adhesion, angiogenesis, and inflammation. Importantly this analysis shows that COUP-TFII plays a role in controlling the expression of inflammatory cytokines. The determination that COUP-TFII plays a role in inflammation may add insight into the role of COUP-TFII in embryo implantation and in endometrial diseases such as endometriosis.

Despite huge increases in access to contraceptives globally more than 700 000 maternal deaths related to unintended pregnancies occurred between 1995 and 2000 mostly in developing countries. Over 80 million women have unintended or unwanted pregnancies annually. Remarkably, there have been no new methods of contraceptives developed in the last 50 years. The extremely high incidence of sexually transmitted infections (STIs) indicates that it is desirable to develop contraceptives that also target STIs. Two interleukin (IL) 6-type cytokines, leukemia inhibitory factor (LIF) and IL11, are obligatory for implantation in mice and are dysregulated in endometrium of some women with infertility. Both LIF and IL11 are also thought to have roles in Chlamydia-induced inflammation which can lead to a multitude of pathologies. LIF and IL11 antagonists were produced and their contraceptive efficacy tested in mice. Polyethylene glycol (PEG) was conjugated to LIF antagonist (LA) or IL11 antagonist (IL11A) to increase their serum half-life. PEGLA injected during the peri-implantation period blocked LIF action in the endometrium and totally prevented embryo implantation while having no embryo toxic effects.1 Similarly, injection of PEGIL11A blocked decidua formation resulting in pregnancy failure.2 In women, vaginally administered drugs preferentially localise to the uterus suggesting that vaginal administration of PEGLA is an appropriate delivery method for contraceptive purposes. Further, vaginally administered PEGLA may be useful as a ‘dual-role’ contraceptive to also block STIs. PEGLA administered via vaginal gel was shown to prevent implantation having minimal effects on non-uterine LIF targets. This is the first study to show the contraceptive efficacy of a PEGylated compound delivered vaginally. It further indicates that PEGLA may be useful as a dual-role contraceptive. Contraceptive trials in non-human primates are currently underway to determine the effect of PEGLA on implantation. If effective, this will offer new opportunities as pharmacological, non-hormonal dual-role contraceptives for women. (1) White CA, Zhang JG, Salamonsen LA, Baca M, Fairlie WD, Metcalf D, Nicola NA, Robb L, Dimitriadis E (2007) Proc Natl Acad Sci USA 104: 19 357–62.(2) Menkhorst E, Salamonsen LA, Robb L, Dimitriadis E (2009) Biol of Reprod 80: 920–927.

The article is devoted to a review of the literature about the thin endometrium and its correction today. The problem of thin endometrium is very significant in cases of unsuccessful embryo implantation. There is no generally accepted approach to the definition of “thin endometrium” and ways of its correction in the literature. Phosphodiesterase type 5 (PDE5) inhibitors are considered to play a role in increasing endometrial thickness and improving pregnancy outcomes. Their action consists of various mechanisms, in particular, such as the induction of vasodilating effect through the effect on signaling to vascular smooth muscle, through the regulation of cell proliferation and induction of angiogenesis by increasing the expression of tumor suppressor factor (p53) and vascular endothelial growth factor A, the inhibition of inflammation by reducing the regulation of proinflammatory cytokines. Although PDE5 inhibitors increase the endometrial thickness through the various mechanisms, especially in women with thin endometrium, it does not necessarily mean that they have a positive effect in all clinical situations. Meanwhile, the successful outcome may be affected by the time of use of the drug, the type of infertility treatment, the main diseases such as pelvic disorders and inflammation. Therefore, there are ambiguous issues that need further research in this problem. Oral PDE5 inhibitors are also used as first-line therapy for the treatment of erectile dysfunction (ED), they have proven effectiveness, tolerability, action and couple satisfaction. Avanafil is the only selective inhibitor of the PDE5 isoenzyme with a low frequency of side effects compared to other drugs in this group. The high tolerability of these drugs has made them an attractive tool for the study of further physiological functions outside the ED with benefits for many non-sexual consequences.

Uterine fibroids are benign tumors of the smooth muscle cells of the uterus that are the most common benign tumors in women during their reproductive years. The etiopathogenesis is multifactorial but we know that mainly estrogen and progesterone induce UF formation and growth. UF vary greatly in size, location, and symptoms: most tumors are largely asymptomatic, but they may also cause a wide range of severe and chronic symptoms that impact negatively with familiar and social relationships. UF might cause infertility. Their adverse effects on pregnancy because distort the endometrial cavity and thin the endometrium. In fact the negative action of fibroids on fertility is mainly due to produce numerous cytokines and growth factors that produce an endometrial inflammation that, with an altered local hormonal environment, may impede embryo-implantation. The type of treatment may depend on the location, size and number of UF and it should be related to understanding if the therapy improves the reproductive capacity of the woman. In this review of the literature we evaluate the various therapeutic possibilities that we have available if we decide to treat UF to improve the fertile capacity of the woman who wishes to have children. We will exclude medical therapy, which is predominantly birth control, although in recent years new substances are being studied, such as vitamin D and epigallocatechin gallate, which promise interesting therapeutic developments. A proper mention will be made of laparotomy, laparoscopic and hysteroscopic myomectomy, but particular importance will be given to the evaluation of new therapeutic trends such as high-intensity focused ultrasound, also guided by nuclear magnetic resonance, and thermal ablation with radio frequency and microwaves. The embolization of UF will also be addressed, but we know it is contraindicated for women who wish to become pregnant.

As the pre-implantation embryo traverses the female reproductive tract, it experiences fluctuations in the composition of the surrounding maternal environment, including the availability of nutrients, growth factors and cytokines. In particular, the cytokine milieu surrounding the early embryo is pivotal in programming optimal embryo development. The pre-implantation embryo is sensitive to a range of perturbations such as maternal diet or in vitro culture. These and other insults influencing the maternal environment including infection, stress and environmental toxins may in part act via impact on oviduct and uterine cytokine synthesis. However the effect of maternal perturbation to inflammation or infection, on the embryo and the role of cytokines in mediating this is not fully elucidated. The studies described in this thesis employed an in vivo mouse model of maternal systemic inflammation with the proinflammatory bacterial lipopolysaccharide (LPS), where a pro-inflammatory cytokine response was elicited on days 2.5 and 3.5 post coitum (pc), prior to implantation. This model was studied in wildtype C57Bl/6 (Il10 ⁺ʹ⁺) mice and mice with a null mutation in the Il10 gene (Il10 ⁻ʹ⁻) were studied to investigate the effects of maternal deficiency in the anti-inflammatory cytokine IL-10 during LPS treatment. We demonstrated that the altered cytokine signals resulting from a low level pro inflammatory LPS challenge (0.5 μg/mouse) in the pre-implantation period elicit changes in the embryo developmental trajectory that in turn alter fetal growth and delay postnatal growth in the male progeny from LPS-treated mothers. As LPS did not directly impact development of the embryo at low and moderate doses, this result appears to reflect indirect effects of LPS mediated via the maternal tract. This is consistent with data from day 3.5 pc oviduct and uterus tissues which revealed increased mRNA expression of proinflammatory cytokines including Il6, Tnfa and Il12b following maternal LPS treatment. Peri-conceptional low dose LPS treatment in Il10 ⁺ʹ⁺ and Il10 ⁻ʹ⁻ mice revealed that the number of viable fetuses and fetal weight were both significantly reduced after LPS treatment, particularly in the Il10 ⁻ʹ⁻ mice. Embryo transfer was then utilised to investigate the mechanism by which LPS acts on the embryo, where day 3.5 pc embryos from donors treated with 0.5 μg LPS or PBS on days 2.5 and 3.5pc were transferred into day 2.5 pc pseudopregnant Swiss female recipients. The effect of maternal LPS treatment on fetal and placental development was seen to be maintained even after embryo transfer, suggesting that any effects of altered cytokine expression in embryos are exerted during cleavage stages before embryo recovery from donors. In addition, postnatal investigation of male and female progeny derived from control PBS and LPStreated Il10 ⁺ʹ⁺ and Il10 ⁻ʹ⁻ females from birth until 19 weeks of age showed that maternal LPS treatment constrains postnatal growth in male progeny regardless of maternal Il10 genotype, compared to male progeny from PBS-treated mothers. While the adult male progeny from LPS-treated Il10 ⁺ʹ⁺ and Il10 ⁻ʹ⁻ mothers did not display changes in fat mass compared to their PBS-treated control counterparts, the combination of maternal LPS treatment and maternal IL-10 deficiency resulted in greater fat mass accumulation in the adult male progeny from LPS-treated Il10 ⁻ʹ⁻ mothers compared to adult male progeny from LPS-treated Il10 ⁺ʹ⁺ mothers. In addition, we investigated the effects of maternal systemic inflammation during the pre-implantation period on the response to LPS challenge during adulthood. Male progeny from LPS-treated Il10 ⁻ʹ⁻ mothers had a dampened response in LIF cytokine following a 100μg/kg LPS challenge at 18 weeks of age. This study implies a role for cytokines as mediators of programming the embryo during the preimplantation period, with altered responses in the event of maternal systemic inflammation impacting on later fetal and postnatal development. The anti-inflammatory cytokine IL-10 acts to protect the embryo from the adverse programming effects of exposure to LPS during the pre-implantation period, with absence of IL-10 resulting in altered postnatal phenotype and particularly fat mass accumulation in the male progeny during adulthood. It appears likely that the absence of IL-10 in the maternal environment delays the clearance of adverse pro-inflammatory cytokines induced during an inflammatory challenge, resulting in prolonged exposure of the embryo to circulating pro-inflammatory cytokines in the maternal tract, supporting a cytokine-mediated mechanism. These studies provide additional evidence for a role of cytokines in embryo sensing of environmental conditions, and indicate that IL-10 is a key regulator of this communication pathway.
Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2014