UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immune cell trafficking and activity are implicated in the parturition process, but little is known about the role of macrophages in control of uterine contractility at term. In the present study, we tested the hypothesis that endotoxin (lipopolysaccharide [LPS]) enhances uterine contractile activity through a mechanism that involves activation of resident macrophages. Various uterotonins and anti-inflammatory mediators were added to a standard muscle bath preparation that contained strips of uterus from Day 15 pregnant C3H/HeN mice. Spontaneous and agonist-induced contractile activity was enhanced following LPS treatment. LPS increased amplitude but not frequency of contractions. Addition of anti-inflammatory cytokines, interleukin 10 or transforming growth factor beta, to suppress macrophage activation did not block LPS-induced increases in contractility. By contrast, indomethacin given to block prostaglandin production suppressed the LPS-induced increase in amplitude of contractions. These findings suggest that an inflammatory response, possibly mediated by activation of macrophages and prostaglandins, participates in the regulation of amplitude but not frequency of contractile activity by the murine uterus before onset of parturition.
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PMID:Effects of endotoxin and macrophage-related cytokines on the contractile activity of the gravid murine uterus. 1277 33

Implantation requires coordination between development of the blastocyst and the sex steroid hormone-regulated differentiation of the uterus. Under the influence of these hormones, the uterine luminal epithelium becomes receptive to attachment of the hatched blastocyst. In this study we sought to identify genes regulated by progesterone (P4) in the uterine epithelium. This resulted in the identification of one novel P4-regulated gene that had been previously found in lipopolysaccharide-stimulated macrophages and called immune response gene-1 (Irg1) and which is the mammalian ortholog of the bacterial gene encoding methylcitrate dehydratase. In adult mice Irg1 expression was limited to the uterine luminal epithelium where it is expressed only during pregnancy with a peak coinciding with implantation. Irg1 mRNA expression is regulated synergistically by P4 and estradiol (E2) but not by E2 alone. In macrophages Irg1 is induced by lipopolysaccharide through a protein kinase C (PKC)-regulated pathway. Now we demonstrate that the PKC pathway is induced in the uterine epithelium at implantation by the synergistic action of P4 and E2 and is responsible for the hormone induction of Irg1. These results suggest that the PKC pathway plays an important role in modulating steroid hormone responsiveness in the uterine luminal epithelium during the implantation window and that Irg1 will be an important marker of this window and may play an important role in implantation.
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PMID:Progesterone regulation of the mammalian ortholog of methylcitrate dehydratase (immune response gene 1) in the uterine epithelium during implantation through the protein kinase C pathway. 1289 84

The anticarcinogenic properties of conjugated linoleic acid (CLA) are, at least partially, attributed to its ability to interrupt the n-6 polyunsaturated fatty acid (PUFA) metabolic pathway for the biosynthesis of eicosanoids, including prostaglandins (PG). Both PGE(2) and PGF(2alpha) play key roles in parturition. In the present study, we compared the effects of CLA (a mixture of cis- and trans-9, 11- and -10, 12-octadecadienoic acid) and linoleic acid (LA) on PG production by cells isolated from maternal intercotyledonary endometrium, fetal allantochorion and amnion from late pregnant ewes. The results demonstrated that supplementation of LA and CLA significantly affected both the proportions and the amounts of PGs produced by all three tissue types. The ability of the uterus and placenta to respond to oxytocin (OT, endometrium only) and lipopolysaccharide (LPS) was also affected. LA inhibited PGE(2) and PGF(2alpha) production in the absence or presence of either oxytocin or LPS. In endometrial cells with or without oxytocin or LPS, CLA dose-dependently suppressed PGF(2alpha) generation, whereas low doses of CLA (20 microM) increased PGE(2) generation. Supplementation with CLA therefore increased the PGE(2)/PGF(2alpha) ratio in the endometrial cells. These results suggest that dietary supplementation of LA or CLA may affect both the initiation and progression of parturition.
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PMID:Effects of conjugated linoleic acid on prostaglandins produced by cells isolated from maternal intercotyledonary endometrium, fetal allantochorion and amnion in late pregnant ewes. 1449 36

The steroid hormone progesterone (P) is a critical regulator of uterine receptivity during blastocyst implantation. The hormone acts through nuclear P receptors (PRs) to modulate the expression of specific gene networks in various uterine cell types. To identify the P-regulated pathways underlying uterine receptivity, we previously used oligonucleotide microarrays to analyze uterine mRNA profiles at the time of implantation in response to RU486, a PR antagonist. We reported that the mRNA corresponding to the immune-responsive gene 1 (Irg1), a previously described lipopolysaccharide-inducible gene, is one of the several mRNAs that are markedly down-regulated by RU486 in the preimplantation uterus. In the present study, we performed in situ hybridization to show that P stimulates Irg1 mRNA synthesis in the luminal epithelial cells of uteri of ovariectomized wild-type but not PR knockout mice. We also report that Irg1 mRNA was induced in the luminal epithelium of pregnant uterus between d 3 and 5, overlapping the window of implantation. To investigate the function of Irg1 during implantation, we administered sense or antisense oligodeoxynucleotides into preimplantation mouse uteri. Treatment with antisense oligodeoxynucleotides led to suppression in Irg1 mRNA expression without affecting unrelated mRNAs in the pregnant uterus. This intervention was also accompanied by impairment in embryo implantation, indicating that the phenotype is linked to the suppression of Irg1 mRNA. Collectively, our studies identified Irg1 as a novel target of PR in the pregnant uterus and also revealed that it is a critical regulator of the early events leading to implantation.
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PMID:Immune-responsive gene 1 is a novel target of progesterone receptor and plays a critical role during implantation in the mouse. 1450 May 77

Preterm birth is a leading cause of neonatal morbidity and mortality. Despite a growing body of evidence correlating inflammation with preterm birth, the signal transduction pathways responsible for the emptying of the uterus in the setting of intrauterine inflammation has not been elucidated. We now report a unique, reproducible mouse model of localized intrauterine inflammation. This model results in 100% preterm delivery with no maternal mortality. Using our model, we also show that platelet-activating factor is a crucial mediator of both inflammation-induced preterm birth and fetal demise. Using C3H/HeJ mice, we demonstrate that toll-like receptor-4 (TLR-4) plays a role in lipopolysaccharide-induced preterm birth but not in inflammation-induced fetal death. Immunohistochemistry studies demonstrate the presence of the platelet-activating factor receptor in both endometrial glands and smooth muscle in uterine tissues. Molecular studies demonstrate the differential expression of platelet-activating factor receptor and TLR-4 in uterine and cervical tissue throughout gestation. Quantitative polymerase chain reaction revealed an up-regulation of TLR-4 in the fundal region of the uterus in response to intrauterine inflammation. The use of this model will increase our understanding of the significant clinical problem of inflammation-induced preterm birth and will elucidate signal transduction pathways involved in an inflammatory state.
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PMID:A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4. 1457 8

Genital tract infections caused by gram-negative bacteria induce abortion and are one of the most common complications of human pregnancy. This study was carried out to decipher the mechanism of gram-negative bacterial lipopolysaccharide (LPS)-induced pregnancy loss, using a mouse (Park strain) model. Since many of the biological effects of LPS are mediated by interleukin (IL)-1alpha, the role of IL-1alpha in LPS-induced pregnancy loss was studied. Pregnant female animals were injected intra-peritoneally (i.p.) with different doses (1 to 50 microg) of LPS from Salmonella minnesota Re-595, on day 0.5 of pregnancy. We found that 250 microg/kg body weight (i.e. 5 microg/female mouse) of LPS when given on day 0.5 of pregnancy was the 'minimum dose' (MD) required to completely inhibit the implantation of the blastocyst in the mouse. The effect of this dose on the pathophysiology of the various reproductive organs (i.e. uterus, ectoplacental cones, developing fetus, ovaries etc.) was assessed on day 14 of pregnancy. The effects of this dose on the level and pattern of expression of the proinflammatory cytokine IL-1alpha in the maternal uterine horns and preimplantation stage embryos were studied by RT-PCR. A single dose (100 ng/mouse) of recombinant mouse IL-1alpha was given i.p. to pregnant females on day 1 of pregnancy to study its effect on implantation. Our results show that treatment of the pregnant animals with LPS may alter cell proliferation and induce leukocyte infiltration, degeneration of luminal glandular epithelium, and hyperplasia in the various reproductive organs, and may also alter both embryonic and uterine IL-1alpha expression. IL-1alpha administration also caused implantation failure similar to that of LPS. The observations suggest that the determined MD of LPS may alter the expression of developmentally important proinflammatory cytokines such as IL-1alpha, which could, in turn, inhibit the normal processes of blastocyst implantation. Therefore, it is proposed that the LPS-induced histopathological alterations in the various reproductive organs of pregnant animals could be mediated by IL-1alpha and this may be one of the causes of failure of blastocyst implantation in the mouse.
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PMID:A 'minimum dose' of lipopolysaccharide required for implantation failure: assessment of its effect on the maternal reproductive organs and interleukin-1alpha expression in the mouse. 1523 66

The molecular biology of lymphatics is only rudimentary owing to the long-standing absence of specific markers, and scanty is the information regarding bladder lymphatic vessels. By using mice with a reporter gene for nuclear factor kappaB (NF-kappaB) activity (kappaB-lacZ) in combination with immunohistochemical staining with a specific lymphatic marker (LYVE-1), we show, for the first time, that NF-kappaB is constitutively active in lymphatic endothelium in the urinary bladder, uterus, intestine, heart, and airways. Tie2-lacZ mice confirmed that the structures observed in kappaB-lacZ mice were not blood vessels. In addition, acute instillation of lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNF-alpha) into the kappaB-lacZ mouse bladder revealed the capacity of this transgenic in reporting inducible NF-kappaB activity. Our findings demonstrate an overriding constitutive NF-kappaB activity in the lymphatic system. They also provide a working model for detecting lymphatic vessels and evoke testable hypotheses regarding the role of lymphatic vessels in health and disease.
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PMID:Visualization of lymphatic vessels through NF-kappaB activity. 1527 2

We investigated the effect of n-6 polyunsaturated fatty acids (PUFAs) on prostaglandin (PG) production by the uterus. A mixed population of endometrial cells (epthelium and stroma) from late-gestation ewes were cultured in defined medium containing linoleic acid (LA, 18:2, n-6), gamma-linolenic acid (GLA, 18:3, n-6) or arachidonic acid (AA, 20:4, n-6) in concentrations of 0 (control), 20 or 100 microM. After 45 h in test medium with or without added PUFAs, cells were challenged with control medium (CM), oxytocin (OT, 250 nM), lipopolysaccharide (LPS, 0.1 micro g/ml) or dexamethasone (DEX, 5 microM) for 22 h in the continued presence of the same concentration of PUFA and the medium was collected for measurement of PGF(2alpha) and PGE(2). Supplementation with LA inhibited the production of PGF(2alpha) but did not alter PGE(2), whereas GLA and AA increased production of both PGs. All PUFA supplements thus increased the ratio of PGE(2) to PGF(2alpha) (E:F ratio) two- to threefold. In control cells, OT and LPS challenges stimulated the production of PGF(2alpha) and PGE(2). In all challenge groups, the concentrations of PGF(2alpha) in response to PUFAs followed the same pattern - LA<control<GLA<AA - but there were significant alterations in responsiveness as a result of PUFA treatment. In the cells supplemented with 100 microM AA, there was no further increase in PGF(2alpha) output in the presence of OT or LPS and when 100 microM GLA was present neither LPS nor OT stimulated PGE(2) significantly. When LPS was given to AA-supplemented cells, the E:F ratio was increased. DEX did not change PGE(2) production in control or LA-treated cells, but the cells produced significantly less PGF(2alpha), so the E:F ratio was increased. In contrast, in GLA- and AA-treated cells, DEX reduced the production of both PGF(2alpha) and PGE(2), so the E:F ratio was unaltered. In summary, the study showed altered production of PGs in the presence of different PUFAs according to their position in the n-6 metabolic pathway. The type of PUFA present affected responsiveness to OT, LPS and DEX and also changed the ratio of PGE(2) to PGF(2alpha) produced. The possible implications of this work are discussed in relation to the effect of diet on term and pre-term labour, which both require upregulation of the endometrial PG synthetic pathway.
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PMID:Alteration of prostaglandin production and agonist responsiveness by n-6 polyunsaturated fatty acids in endometrial cells from late-gestation ewes. 1528 85

In bitches, the onset of pyometra, an infection of the uterus, characteristically occurs in the first half of the diestrous stage in the estrous cycle, in which the blood concentration of progesterone peaks and that of estradiol-17beta is lowest. To investigate the immunological mechanisms governing stage-specific onset of pyometra, peripheral blood mononuclear cells (PBMNCs) were collected from beagle bitches during different stages of the estrous cycle and examined using various immunological assays. When we examined the proliferative response of PBMNCs to PYO-252, that is a clone of Escherichia coli isolated from the uterus of a dog afflicted with pyometra, the response of PBMNCs significantly decreased in the first half (day 10) of diestrus, but increased in proestrus/estrus. No significant differences were observed in the responses to concanavaline A between stages of the cycle. Throughout the estrous cycle, canine PBMNCs did not respond to lipopolysaccharide derived from E. coli. The response of PBMNCs collected in anestrus to PYO-252 was significantly enhanced upon the addition of estradiol-17beta to the culture. In contrast, these responses were significantly suppressed in the presence of progesterone. Progesterone progenitor or metabolite molecules, which have a low affinity for the progesterone receptor, did not affect proliferative responses. Expression of gamma interferon (IFNgamma) in response to PYO-252 was also significantly enhanced by estradiol-17beta, but suppressed by progesterone. This evidence suggests that in the first half of the diestrous stage, suppressed activity of cellular immunity results from increasing progesterone concentration and minimal estrogen release. This marked decrease of immune resistance allows the expansion of E. coli, which enter the uterine cavity through the loosened cervical canal during estrus, leading to pyometra onset.
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PMID:Effect of ovarian hormones on periodical changes in immune resistance associated with estrous cycle in the beagle bitch. 1563 30

Polyunsaturated fatty acids derived from the diet are incorporated into cell membranes where they act as precursors for prostaglandin (PG) synthesis. Linoleic acid (LA; 18:2 n-6) is a major constituent of plant oils and its consumption in Westernized populations is increasing. This study investigated the influence of LA on PG production by the uterus and placenta. Pregnant ewes were fed a control or an LA-enriched diet. Oxytocin (OT) was injected on day 45 (early) or day 133 (late) of gestation to measure the release of 13,14-dihydro-15-keto PGF(2alpha) (PGFM). Ewes were killed on day 46 or day 138 for collection of uterine intercaruncular endometrium and fetal allantochorion. Basal and stimulated PG release from explant cultures was assessed before and after in vitro treatment with OT, lipopolysaccharide (LPS), dexamethasone (DEX) or calcium ionophore (CaI). Expression of cyclooxygenase (COX)-1 and COX-2 was determined by Western blot in endometrium of late-gestation ewes. Circulating PGFM levels in vivo did not differ according to diet but there were highly significant differences in the release of PGs in vitro. Basal production of PGF(2alpha)and PGE(2) by the endometrium and of PGE(2) by the allantochorion were all higher in tissues from LA-supplemented ewes. Endometrial tissues produced more PG following OT and CaI treatment, whereas DEX inhibited production of both PGs at both stages of gestation. In allantochorion collected at day 46 LPS did not significantly alter PGE(2) release and DEX increased output, whereas at day 138 LPS was stimulatory but DEX was inhibitory. These data show that a high-LA diet can significantly increase the ability of both endometrium and placental tissues to produce PGs in vitro. This effect of diet may only become apparent after a sustained period of PG release, so was not seen following the brief pulse caused by OT treatment in vivo. As COX protein levels were unaltered, the main influence was likely to be via conversion of LA to arachidonic acid, providing an increased supply of precursor. These results support previous studies which suggest that alterations in dietary polyunsaturated fatty acids may influence the time of labour.
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PMID:The effect of a diet supplemented with the n-6 polyunsaturated fatty acid linoleic acid on prostaglandin production in early- and late-pregnant ewes. 1564 93

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