Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01178 (oxytocin)
 15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PGs are important regulators of reproductive processes. At the time ofluteolysis in vivo, PGF2alpha is produced by endometrial cells, in response to oxytocin (OT). The mechanism by which OT induces the release of PGF2alpha remains to be defined. We have used 13 different cultures of bovine epithelial endometrial cells to study the effect of OT on the regulation of PGF2alpha and to identify the possible involvement of cyclooxygenases (COXs). OT induced a dose-dependent increase of both inositol phosphates (IPs) and [Ca2+]i concentration in epithelial cells labeled with [3H]-myoinositol or loaded with fura-2 (using a fluorescent microscope imaging system), respectively. OT induced a dose-dependent increase of both PGF2alpha production and COX-2 gene expression (as demonstrated by RT-PCR and Northern blots). PGF2alpha production was increased from 13.3 +/- 2.0 to 166.8 +/- 22.5 ng/ml (P < 0.0001). On the other hand, COX-2/beta-actin mRNA gene expression (as determined by densitometric analysis) was increased 5.1 +/- 0.7-fold (P < 0.001) with OT (10[-7] M) treatment, compared with control. Addition of indomethacin (1 microM) and a specific COX-2 inhibitor (NS-398, 1 microM) blocked the OT-induced PGF2alpha production. COX-1 and phospholipase A2 mRNA were expressed at steady-state levels, but no effect of OT was detected on their regulation. Combined to OT, 10 microq/ml of recombinant ovine interferon-tau (roIFN-tau) was able to decrease significantly (P < 0.0001) the dose-dependent increase of PGF2alpha production. Furthermore, partial bovine COX-1 (777 pb) and COX-2 (449 bp) cDNAs were cloned and sequenced. An homology of 83% and 97% was found in relation with rat and sheep, for COX-1, respectively. COX-2 was found to bear 84%, 86%, and 87% of homology in relation to rat, guinea pig, and human, respectively. Collectively, these results demonstrate, for the first time, that COX-2 is involved in the mechanism by which OT regulates PGF2alpha production in the endometrium.
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PMID:Cellular mechanisms involved during oxytocin-induced prostaglandin F2alpha production in endometrial epithelial cells in vitro: role of cyclooxygenase-2. 934 8

Cyclooxygenase 1 and 2 (COX-1 and COX-2) mRNA were measured by ribonuclease protection assays in total RNA extracted from intercaruncular and caruncular endometrium, myometrium, cotyledons, and cervical mucosa of pregnant cows. Tissues were obtained at gestational ages of 150 days and 275 days and at term not in labor, at term in labor, and 6-12 h postpartum. Additionally, the effect of oxytocin (OT) on COX-2 expression was determined in intercaruncular endometrium of six third-trimester cows (between 230 and 270 days of pregnancy), three of which were injected with OT (200 IU) and three with saline 2 h before tissues were harvested. Prostaglandin F2alpha (PGF2alpha) metabolite was measured in plasma samples taken at 15-min intervals before and after the injections. Results showed that COX-2 mRNA was expressed in every type of tissue examined, although in different concentrations and beginning at different stages. Other than in seminal vesicular and prostate glands used as positive controls, low concentrations of COX-1 mRNA were detected only in myometrium and caruncles. Cotyledons had the highest concentration of COX-2 transcripts at all stages studied. Caruncles had about half the concentration of COX-2 transcripts that was seen in cotyledons, and on Day 150 even less. COX-2 mRNA expression in both tissues increased with advancing gestation, but there was no difference between samples from term-no-labor and term-in-labor cows. COX-2 mRNA concentrations in endometrium and myometrium were low; they varied randomly during pregnancy with no significant increase until postpartum, when COX-2 transcripts in endometrium had increased severalfold whereas those in myometrium were similar to values before parturition. Cervical mucosa expressed COX-2 mRNA weakly until term but had increased markedly at parturition. Injection of 200 IU of OT induced a substantial increase in endometrial COX-2 mRNA concentration within 2 h; this was associated with linearly increasing plasma concentrations of 13, 14-hydroxy-15-keto-prostaglandin F2alpha, which were still rising at termination of the experiment. The results suggest that endogenous OT is a major factor in induction of COX-2 expression and PGF2alpha release at term and during parturition in cows.
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PMID:Accumulation of cyclooxygenase-2 gene transcripts in uterine tissues of pregnant and parturient cows: stimulation by oxytocin. 991

Myometrial contractions of labor result from an increase in myometrial activation and stimulation. Activation develops through the expression of contraction associated proteins (CAPs), including oxytocin receptors (OTR), connexin-43 (Cx-43), and prostaglandin F2 alpha, receptors (FP). Stimulation involves increases in contractile agonists including prostaglandin E2 (PGE2) and prostaglandin F2 alpha. (PGF2 alpha) that may result from increases in prostaglandin endoperoxide H synthase (PGHS)-2. A mouse model of preterm birth was used to study gene expression involved in myometrial activation and stimulation. To induce preterm birth, pregnant C57BL/6J mice were intubated with 6 g/kg ethanol on gestational day 16 and were killed every 6 h from treatment until birth. RIA was used to measure uterine PGE2 and PGF2 alpha, while PGHS-2, OTR, Cx-43, and FP messenger RNA levels were measured by ribonuclease protection assay. Increases in CAP mRNA were associated with term and preterm birth. There were differences in stimulation effectors associated with preterm and term birth. Uterine PGF2 alpha values were increased only at the time of term birth, but PGE2 was elevated during both preterm and term labor. These data suggest that existing levels of PGF2 alpha are sufficient for preterm birth when CAP expression is increased, but term labor requires increases in PGE2, PGF2alpha, and CAPs. The PGHS-2 messenger RNA expression pattern suggests that it is a CAP.
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PMID:Expression of myometrial activation and stimulation genes in a mouse model of preterm labor: myometrial activation, stimulation, and preterm labor. 1080 82

In the present study we have shown that the genetic expression of prostaglandin (PG)F(2alpha) receptor (R) and cyclooxygenase (COX)-2 increases in laboring rat myometrium. This finding was associated with a relatively weak contractile in vitro response (E:(max)) of isolated uterine strips when challenged with PGF(2alpha). Five days postpartum PGF(2alpha)-R mRNA values exceeded those during labor while COX-2 mRNA was reduced to preparturient values. Maximal contractility of isolated strips stimulated with PGF(2alpha) at this time was enhanced and E:C(50) decreased. Oxytocin treatment of estrogen-primed nonpregnant rats down-regulated uterine contractile responsiveness to PGF(2alpha), leaving mRNA values for this receptor unchanged, whereas oxytocin receptor blockade with atosiban (an oxytocin receptor antagonist) left E:(max) unaltered. In contrast, atosiban treatment of pregnant rats resulted in a 2.5-fold increase in E:(max) and a considerably reduced EC(50) during labor when compared to untreated delivering rats. The increased contractile ability was associated with a threefold increase in PGF(2alpha)-R mRNA production, indicating that the regulation by atosiban of the PGF(2alpha)-induced response is exerted at the genetic level. Based on the present data we suggest that 1) PGF(2alpha)-R stimulation may not primarily exert a contracting role in the normally delivering myometrium, and 2) the presence of the PGF(2alpha)-R system in rat myometrium may explain the apparent functional redundancy of the oxytocinergic system during the process of birth in animals lacking oxytocin or where the oxytocin receptor is blocked. In this context PGF(2alpha) receptor stimulation may, in the absence of oxytocin receptor stimulation, exert the contractile forces needed for proper propulsion of the fetus.
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PMID:Effect of oxytocin receptor blockade on rat myometrial responsiveness to prostaglandin f(2)(alpha). 1105 50

This study was conducted to determine whether early progesterone treatment plays a role in the regulation of messenger RNA (mRNA) expression for oxytocin-neurophysin, oxytocin receptor, prostaglandin G/H synthase (PGHS)-1 and PGHS-2 in the ovine corpus luteum. The expression of ovarian oxytocin, oxytocin receptor, PGHS-1 and PGHS-2 mRNA was investigated in control, progesterone- or RU486-treated ewes. Fifteen ewes were randomly assigned to three groups to receive intramuscular injections of progesterone (12.5 mg; n = 5), RU486, (2.5 mg kg(-1) bodyweight; n = 4) or corn oil (1 mL; n = 6) twice daily from Day 1 to Day 3 post oestrus. On the morning of Day 4 post oestrus, the corpora lutea were collected and analysed for oxytocin-neurophysin mRNA by Northern blot using a labelled cDNA probe, and for the expressions of the oxytocin receptor, PGHS-1 and PGHS-2 mRNA using the reverse transcription polymerase chain reaction. Administration of progesterone or suppression of progesterone activity with RU486 did not affect expression of oxytocin-neurophysin mRNA (P>0.05). Pretreatment of the ewes with progesterone resulted in the enhancement of luteal oxytocin receptor mRNA expression and suppression of PGHS-1 and PGHS-2 mRNA (P<0.001). These results indicate that early progesterone treatment does not control the expression of oxytocin-neurophysin mRNA in the ovine ovary but may be involved in the regulation of ovarian oxytocin receptor and PGHS expression. It is proposed, on the basis of these results, that progesterone may play a role in premature corpus luteum regression through an intra-ovarian mechanism involving the induction of ovarian oxytocin receptor mRNA expression.
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PMID:Effects of progesterone on expression of messenger RNA encoding oxytocin-neurophysin, oxytocin receptor and prostaglandin G/H synthase-1 and -2 during the early oestrous cycle in the ovine corpus luteum. 1110 Dec 80

We used an animal model to study uterine leiomyoma in the context of pregnancy-associated changes in gene expression and to determine how they might modulate tumor growth. Spontaneous tumors and normal myometrium were collected from Eker rats and compared with myometrial samples from pregnant animals. A leiomyoma-derived cell line was also used to assess pregnancy-related changes in gene expression and to determine the impact of signaling by the oxytocin receptor. Eker rat leiomyomas expressed several pregnancy-related genes, including connexin 43, oxytocin receptor (OTR), and cyclooxygenase (COX)-1; however, the tumors did not express COX-2, which is expressed in the parturient myometrium. The leiomyoma-derived cell lines also expressed OTR, which responds to estrogen, binds to oxytocin, and exhibits a calcium flux when stimulated with oxytocin. The OTR signaling mediated by oxytocin inhibited estrogen-stimulated growth of leiomyoma cells. Leiomyoma cells expressed many genes of the parturient myometrium, including OTRs, but were deficient in COX-2 expression. Signaling via the OTR appears to inhibit estrogen-induced cell proliferation, suggesting that signaling by this receptor might help mediate the protective effect of pregnancy on this disease.
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PMID:Uterine leiomyomas express myometrial contractile-associated proteins involved in pregnancy-related hormone signaling. 1251 88

In ruminants, interferon produced by the trophectoderm (IFN-tau) is recognized as the embryonic signal responsible for maternal recognition of pregnancy. IFN-tau is believed to act by down-regulating estrogen receptors, thus preventing appearance of oxytocin receptors responsible for the release of prostaglandin F(2alpha) (PGF(2alpha)) by the endometrium. The present study was undertaken to determine in vitro the biological activities of different IFN-tau isoforms and document putative alternate luteotrophic mechanisms. Endometrial cells in primary cultures were treated with five different rIFN-tau isoforms: two ovine isoforms (ro-4 and ro-11) and three bovine isoforms (rb-1a, rb-2b and rb-3b). Their effect was quantified by measurement of PGE(2) and PGF(2alpha) production by ELISA and induction of cyclooxygenase (COX-2) by Western and Northern analysis and correlated with antiviral activity previously reported. The overall pattern of response to the IFNs tested suggests that low concentrations (<1 microg/ml) reduced the production of both PGs and higher concentrations (>1 microg/ml) stimulated preferentially PGE(2); however, exceptions were noted. Isoform rb-2b with high antiviral activity inhibited PG production in both cell types at all concentrations tested. IFNs rb-1a and ro-11 had similar antiviral activities, inhibiting PG at low concentrations and stimulating them at high concentrations. Isoform rb-3b stands out relative to the other IFNs tested because it induced a variable non-dose-dependent effect on PG production and low antiviral activity. An increase in COX-2 protein expression and messenger was correlated with increased PG production. The results showing two distinct responses to IFN-tau depending on its concentration and/or isoform and the absence of correlation with antiviral activity suggest that complex transduction mechanisms are involved.
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PMID:Influence of different isoforms of recombinant trophoblastic interferons on prostaglandin production in cultured bovine endometrial cells. 1260 58

In sheep, the uterus produces luteolytic pulses of prostaglandin F2alpha (PGF) on Days 15 to 16 of estrous cycle to regress the corpus luteum (CL). These PGF pulses are produced by the endometrial lumenal epithelium (LE) and superficial ductal glandular epithelium (sGE) in response to binding of pituitary and/or luteal oxytocin to oxytocin receptors (OTR) and liberation of arachidonic acid, the precursor of PGF. Cyclooxygenase-one (COX-1) and COX-2 are rate-limiting enzymes in PGF synthesis, and COX-2 is the major form expressed in ovine endometrium. During pregnancy recognition, interferon tau (IFNtau), produced by the conceptus trophectoderm, acts in a paracrine manner to suppress development of the endometrial epithelial luteolytic mechanism by inhibiting transcription of estrogen receptor alpha (ERalpha) (directly) and OTR (indirectly) genes. Conflicting studies indicate that IFNtau increases, decreases or has no effect on COX-2 expression in bovine and ovine endometrial cells. In Study One, COX-2 mRNA and protein were detected solely in endometrial LE and sGE of both cyclic and pregnant ewes. During the estrous cycle, COX-2 expression increased from Days 10 to 12 and then decreased to Day 16. During early pregnancy, COX-2 expression increased from Days 10 to 12 and remained higher than in cyclic ewes. In Study Two, intrauterine infusion of recombinant ovine IFNtau in cyclic ewes from Days 11 to 16 post-estrus did not affect COX-2 expression in the endometrial epithelium. These results clearly indicate that IFNtau has no effect on expression of the COX-2 gene in the ovine endometrium. Therefore, antiluteolytic effects of IFNtau are to inhibit ERalpha and OTR gene transcription, thereby preventing endometrial production of luteolytic pulses of PGF. Indeed, expression of COX-2 in the endometrial epithelia as well as conceptus is likely to have a beneficial regulatory role in implantation and development of the conceptus.
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PMID:Effects of the estrous cycle, pregnancy and interferon tau on expression of cyclooxygenase two (COX-2) in ovine endometrium. 1295 85

Estradiol (E2), progesterone (P4), and oxytocin (OT) are important for the initiation of luteolysis in ruminants but the mechanisms involved are still poorly understood. The objective of this study was to determine if duration of exposure of bovine endometrial epithelial cells to P4 affected the response of the cells to E2. Endometrial epithelial cells, from cows at Days 1-3 of the estrous cycle, were cultured for 10, 17, and 21 days in the presence or absence of P4 (100 ng ml(-1)). After culture, each group of cells was incubated for a further 6, 12, 24 or 48 h with or without E2 (100 pg ml(-1)) and then incubated for 6 h with different doses of OT (2, 20, and 200 ng ml(-1)). E2 enhanced OT-stimulated PGF2 alpha secretion in cells cultured with P4 for 17 or 21 days, with a maximum effect after 24-h exposure, but not in cells cultured with P4 for 10 days. To determine the mechanism of action of E2, COX-1 and COX-2 were measured by Western blotting and OTR number was measured by saturation analysis. OT increased COX-2 (P<0.05), but there was no significant effect of E2 on the expression of either COX-1 or COX-2. E2 did, however, increase (P<0.001) the OTR number in cells cultured with P4 for 21 days, whereas it inhibited OTR in cells cultured for 10 days. These data show that E2 can stimulate PGF2 alpha secretion by increasing OTR expression in bovine endometrial cells in vitro, but only after exposure to P4.
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PMID:Prolonged progesterone treatment of endometrial epithelial cells modifies the effect of estradiol on their sensitivity to oxytocin. 1295 70

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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