Soluble HLA-G influences the release of cytokines from allogeneic peripheral blood mononuclear cells in culture.
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Exquisitely regulated cytokine balance during early pregnancy is thought to be necessary for promoting survival of the fetal allograft. Our previous studies have demonstrated that membrane-bound human leukocyte antigen (mHLA-G) expressed on trophoblasts is one of the key factors in regulating cytokine balance by shifting the Th1/Th2 balance toward Th2 polarization, a favourable milieu for the maintenance of pregnancy. Given that trophoblasts secrete soluble HLA-G (sHLA-G), we examined its biological roles in comparison with mHLA-G. We cultured peripheral blood mononuclear cells (PBMC) with either the HLA-A and -B-deficient B lymphoblast cell line (721.221 cells) or the same cell line transfected with mHLA-G (721.221-G1 cells), in the presence or absence of recombinant sHLA-G. Cytokine concentrations in the culture media were determined by enzyme-linked immunosorbent assay. In contrast to mHLA-G protein, sHLA-G stimulated the release of tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, whereas it reduced the release of interleukin (IL)-3, regardless of the presence of the presence of a stimulatory effect of the mHLA-G-expressing cells. Although mHLA-G reduced the release of IL-4, sHLA-G did not have any effect. Conversely, sHLA-G stimulated the release of IL-10 whereas mHLA-G was without effect. These results suggest that sHLA-G regulates the release of cytokines from PBMC chiefly by counterbalancing mHLA-G, and thereby may play a role in maintaining pregnancy. (+info)
Glutathione S-transferase M1 and T1 polymorphisms and the risk of recurrent pregnancy loss.
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The aetiology of recurrent pregnancy loss (RPL) remains unclear, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We examined the relation between RPL and polymorphisms in two genes, glutathione S-transferases (GST) M1 and T1, which are involved in the metabolism of a wide range of environmental toxins and carcinogens. A case-control study of 115 cases with RPL and 160 controls was conducted. All cases and controls were women resident in Sapporo, Japan and the surrounding area. They were genotyped for polymorphisms of GSTM1 and GSTT1 using PCR-based methods. We found that 65.2% of the cases with RPL and 45.6% of the controls had the GSTM1 null genotype [odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.36-3.66]. On the other hand, 47.0% of the cases and 49.4% of the controls had the GSTT1 null genotype (OR = 0.95; 95% CI = 0.58-1.55). The results suggest that women with GSTM1 null polymorphism may therefore have an increased risk of RPL. (+info)
Polyunsaturated fatty acids and bovine interferon-tau modify phorbol ester-induced secretion of prostaglandin F2 alpha and expression of prostaglandin endoperoxide synthase-2 and phospholipase-A2 in bovine endometrial cells.
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Embryonic mortality in cattle may occur because of inadequate inhibition of uterine secretion of prostaglandin (PG) F2alpha mediated by bovine interferon-tau (bIFN-tau). The objectives of the present study were to determine whether polyunsaturated fatty acids inhibit secretion of PGF2alpha from bovine endometrial cells induced by stimulating protein kinase C with phorbol 12,13 dibutyrate (PDBu) and to investigate possible mechanisms of action. Confluent cells were exposed for 24 h to 100 microM of linoleic, arachidonic (AA; C20:4, n-6), linolenic (LNA; C18:3, n-3), eicosapentaenoic (EPA; C20:5, n-3), or docosahexaenoic (DHA; C22:6, n-3) acid. After incubation, cells were washed and stimulated with PDBu. The EPA, DHA, and LNA attenuated secretion of PGF2alpha in response to PDBu. The EPA and DHA were more potent inhibitors than LNA. The EPA inhibited secretion of PGF2alpha at 6.25 microM. Secretion of PGF2alpha in response to PDBu decreased with increasing incubation time with EPA. Both bIFN-tau and EPA inhibited secretion of PGF2alpha, and their inhibitory effects were additive. The bIFN-tau, but not EPA, reduced the abundance of PG endoperoxide synthase-2 (PGHS-2) mRNA. Incubation with 100 microM EPA, DHA, or AA for 24 h followed by treatment with PDBu did not affect concentrations of PGHS-2 and phospholipase A2 proteins. The EPA and DHA inhibit secretion of PGF2alpha through a mechanism different from that of bIFN-tau. The effect of EPA on PGF2alpha secretion may be caused by competition with AA for PGHS-2 activity or reduction of PGHS-2 activity. The use of EPA and DHA to inhibit uterine secretion of PGF2alpha and to improve embryonic survival in cattle warrants further investigation. (+info)
Possible expansion of "Window of Implantation" in pseudopregnant mice: time of implantation of embryos at different stages of development transferred into the same recipient.
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Blastocyst implantation and successful establishment of pregnancy require delicate interactions between the embryo and maternal environment. It is believed that the growth of transferred embryos of different ages is synchronized during preimplantation development and that such embryos are implanted in the uterus at the same time. To define the time of synchronization for developing embryos of different ages, embryos at two different stages of development were transferred separately into the oviducts of the same recipient. We then examined the subsequent development of the embryos at various time intervals after transfer. Pronucleus (PN) stage eggs were transferred separately to the right or left oviduct of recipients on Day 0, while eight-cell embryos (8C) were transferred to the other oviduct. For 8C, 5%, 63%, and 74% of transferred embryos were implanted in the uterus at 42, 66, and 90 h posttransfer, respectively. In contrast, none of the transferred PN was implanted until 90 h posttransfer. At 90 h posttransfer, 59% of the PN had successfully implanted. Histological examination revealed that developmental stage of the embryos in both groups synchronized around 162 h posttransfer, even though the implantation was accelerated in 8C compared with PN. Our results indicate that embryos of advanced stage transferred to the oviduct implant in the uterus in advance of younger embryos and that the uterine development is synchronized at the neural plate, presomite stage. Our results strongly suggest that uterine receptivity for implantation is expandable in pseudopregnant mice. (+info)
Expression of membrane-bound HLA-G at the maternal-fetal interface is not associated with pregnancy maintenance among patients with idiopathic recurrent pregnancy loss.
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Recurrent pregnancy loss (RPL) has many known aetiologies. However, using current diagnostic testing, a large fraction of recurrent pregnancy losses remain unexplained. Many of these may have immune underpinnings. HLA-G is a non-classical MHC class I product whose fairly restricted expression at the maternal-fetal interface suggests a role in successful embryonic implantation and/or subsequent pregnancy maintenance. The study of immune-mediated RPL should be enhanced by comparing groups of idiopathic RPL patients with normal fetal chromosomes to RPL patients with known chromosomal abnormalities in their index pregnancies. We hypothesized that if alteration of HLA-G expression at the maternal-fetal interface were associated with immune-mediated RPL, such changes might be detectable using these comparisons. HLA-G protein expression at the maternal-fetal interface in maternal and gestational age-matched women with history of idiopathic RPL and normal male fetuses were compared with expression in RPL patients with known fetal trisomy 16 in their index pregnancy. We detected no significant quantitative differences in the levels of HLA-G between these groups of RPL patients. Within the limitations of this study, we conclude that HLA-G expression is not a major immunological determinant of pregnancy maintenance among patients with idiopathic RPL. (+info)
Effect of 1,25-dihydroxyvitamin D3 on the female reproductive system in rats.
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Parenteral application of the active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3, has been anticipated to have remarkable efficacy in secondary hyperparathyroidism. However, in a reproduction seg. I study in rats, poor reproductive performance was reflected in a decrease in the number of matings, implantations and live births. These changes were though reversible after treatment with the compound was discontinued. In order to clarify the mechanism of these reversible toxicities, the following were examined in female rats treated with the D3 metabolite: 1. effect on the estrous cycle (no treatment for 2 weeks, treatment for 3 weeks and recovery for 2 weeks), and 2. effect on the maintenance of pregnancy (treatment for 2 weeks before mating and during the gestation period). In both groups, the levels of calcium, calcitonin, PTH and progesterone in serum were measured, and histopathological examination of the thyroid, parathyroid, ovary and uterus was carried out. The following results were observed: 1) disturbance of the estrous cycle, 2) hypofunctional changes in the corpus luteum in the ovary, and the epithelium, endometrium and uterine gland in the uterus with a decrease in the serum progesterone level and 3) hypercalcemia with a decrease in calcitonin or PTH levels in serum with morphological changes including atrophy and cyst-formation in the parathyroid. However, the above changes were reversible, and recovery was observed after administration of the compound was discontinued. These results indicate that the hypercalcemia caused by 1,25-dihydroxyvitamin D3 disrupts endocrinological homeostasis which in turn temporarily disrupts the female reproductive system. Furthermore, it was suggested that 1,25-dihydroxyvitamin D3 itself directly influences on endocrinological organs (hypothalamus, pituitary, parathyroid and thyroid) and reproductive organs (ovary and uterus). (+info)
Fetal and maternal transforming growth factor-beta 1 may combine to maintain pregnancy in mice.
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One of the mysteries of pregnancy is why a mother does not reject her fetuses. Cytokine-modulation of maternal-fetal interactions is likely to be important. However, mice deficient in transforming growth factor-beta1 (TGF beta 1) and other cytokines are able to breed, bringing this hypothesis into question. The phenotype of TGF beta 1 null-mutant mice varies with genetic background. We report here that, in outbred mice, the loss of TGF beta 1-deficient embryos is influenced by the parity of their mother. This is consistent with the loss of mutants being due to immune rejection. An inbred line of TGF beta 1(+/-) mice that supported TGF beta 1-deficient fetuses had high levels of TGF beta 1 in their plasma. Analysis of the amniotic fluids in this line indicated that biologically relevant levels of maternal TGF beta 1 were present in the TGF beta 1(-/-) fetuses. These data are consistent with maternal and fetal TGF beta 1 interacting to maintain pregnancy, within immune-competent mothers. (+info)
Depletion of CD8+ cells abolishes the pregnancy protective effect of progesterone substitution with dydrogesterone in mice by altering the Th1/Th2 cytokine profile.
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One of the most remarkable immunological regulations is the maternal immune tolerance toward the fetal semiallograft during pregnancy, which has been referred to as immunity's pregnant pause. Rejection of the semiallogeneic trophoblast cells must be selectively inhibited and pathways presumably include Th2 cytokines unopposed by Th1 cytokines. Steroid hormones, including progesterone, have similar effects. Low levels of progesterone and Th2 cytokines and high levels of Th1 cytokines are attributable for increased abortions in mammalians, which may be triggered by psychoemotional stress. Thus, the aim of the present study was to provide experimental evidence for the mechanism involved in the mediation of immune responses by endocrine signals during pregnancy and stress-triggered pregnancy failure. DBA/2J-mated CBA/J female mice were randomized in three groups: 1) control females, 2) mice exposed to stress on gestation day 5.5, and 3) mice exposed to stress and substituted with dydrogesterone, a progestogen with a binding profile highly selective for the progesterone receptor on gestation day 5.5. On gestation days 7.5, 9.5, and 10.5, mice of each group were sacrificed, and the frequency of CD8(+) cells and cytokine expression (IL-4, IL-12, TNF-alpha, IFN-gamma) in blood and uterus cells was evaluated by flow cytometry. Additionally, some mice were depleted of CD8 cells by injection of mAb. We observed that progesterone substitution abrogated the abortogenic effects of stress exposure by decreasing the frequency of abortogenic cytokines. This pathway was exceedingly CD8-dependent, because depletion of CD8 led to a termination of the pregnancy protective effect of progesterone substitution. (+info)