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Articles |
a Département d'Ontogénie et Reproduction, Centre de Recherches du Centre Hospitalier de l'Université Laval (CHUL),
b Centre de Recherche en Biologie de la Reproduction (CRBR) and Département d'Obstétrique et Gynécologie, Université Laval, Ste-Foy, Québec, Canada G1V 4G2
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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play important roles in which they often exert opposite effects. At the time of recognition of pregnancy in vivo, PGF2 is recognized as the luteolytic factor in ruminants and in most species including human, whereas PGE2 may exert a luteoprotective action. We have previously demonstrated that recombinant interferon-tau (rIFN-
), the embryonic signal responsible for recognition of pregnancy in ruminants, stimulated in vitro the production of PGE2 and prostaglandin-endoperoxide synthase 2 (Ptgs2; also called cyclooxygenase-2) gene expression in both epithelial and stromal endometrial cells. Since PGE2 is the major prostaglandin produced by stromal cells, the effect on Ptgs2 could explain the increase in PGE2 output. At high concentrations, however, recombinant ovine (ro) IFN- acts on epithelial cells by changing the primary PG produced from PGF2 to PGE2. This change in the primary PG produced could be explained by a decrease in PGF synthase (PGFS) activity or an increase in PGE synthase activity, or by modulation of a putative PGE2–9-ketoreductase, which converts PGE2 into PGF2. Therefore, we have investigated the regulation of the mRNAs for PGFS and PGE2-9-ketoreductase (9K-PGR), two enzymes that lead to the production of PGF2. Others have described 9K-PGR activity in uterus, ovaries, kidney, and liver of different species and have established that this enzyme could possess both 9K-PGR and 20-hydroxysteroid dehydrogenase (20-HSD) activity. Some have concluded that 9K-PGR and 20-HSD are identical enzymes. Using primers sequences chosen from homologous nucleotide sequences of published rabbit 20-HSD/9K-PGR and rat 20-HSD cDNAs, a 317-base pair (bp) fragment was amplified by reverse transcription-polymerase chain reaction (RT-PCR), cloned, and sequenced. Homologies of 83% and 78% were found with rabbit and rat 20-HSD, respectively. The presence of 20-HSD/9K-PGR and prostaglandin F synthase (PGFS) mRNA expression was studied semiquantitatively in cultured epithelial cells using RT-PCR. Stimulation of cells with roIFN-t resulted in a biphasic response, an inhibition of PGF2 production at low dose (1 ng/ml) and a stimulation of PGE2 at high dose (10 µg/ml). The increase of PGE2 was accompanied by reduced 9K-PGR and PGFS mRNA gene expression. The effect of oxytocin (OT) was also studied, and the presence of OT had no effect on either 9K-PGR or PGFS gene expression. The 20-HSD/9K-PGR transcript was also detected in other bovine tissues at different intensity (liver > kidney > testis > ovaries). We believe that the 9K-PGR and PGFS can be key enzymes in the regulation of specific PGs in the endometrium during the periimplantation period.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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of uterine origin is responsible for luteolysis and the return to the estrous cycle. In ruminants, identification of the uterus as the source of luteolytic PGF2 has been submitted to strict requirements where PGF2 is regulated by luteal oxytocin (OT) by a positive feedback loop [1,2]. On the contrary, PGE2 may have anti-luteolytic and/or luteotrophic properties. In ruminants, IFN- serves as the embryonic signal and is produced in large amounts by the conceptus (embryo and associated membranes) during the preimplantation period [3,4]. Using primary endometrial cell cultures, we have shown that epithelial cells were the primary source of PGF2, and stromal cells were the primary source of PGE2 [5]. Recently, we have demonstrated that recombinant ovine interferon-tau (roIFN-) stimulated PGE2 production [6,7] and prostaglandin-endoperoxide synthase 2 (Ptgs2; inducible form) but not Ptgs1 (constitutive form) or phospholipase A2 (Pla2) gene expression in both epithelial and stromal endometrial cells in vitro [8]. Even though our results showing that the presence of roIFN- decreased OT-induced PGF2 production [6,9] were confirmed using recombinant bovine (rb) IFN- [10], the mechanism by which IFN- stimulates PGE2 production in epithelial cells remains intriguing. Indeed, since the major prostaglandin produced by stromal cells is PGE2, the stimulatory effect observed on Ptgs2 can explain the increase in PGE2 in response to roIFN- in these cells. However, in epithelial cells, under unstimulated conditions, PGF2 is the major PG produced. Thus, IFN- acts on epithelial cells by changing the primary PG produced from PGF2 to PGE2. Selective stimulation of PGE2 following Ptgs2 activation has also been reported in rat peritoneal macrophages [11]. An action at the level of Ptgs2 is not sufficient to explain the selective change in the PG produced in epithelial cells, unless cellular compartmentalization of Ptgs1 and Ptgs2 functionally coupled to PGE synthase within the cell allows preferential synthesis of PGF2 or PGE2, respectively. This has been postulated to justify the presence of two different PGHS wherein Ptgs1 is associated with the endoplasmic reticulum and is involved in the generation of PGs aimed at autocrine or paracrine "housekeeping" actions through extracellular receptors and second messengers, whereas Ptgs2, localized on the nuclear envelope, would generate PGs aimed at gene regulation [12]. This mechanism is unlikely in endometrial cells, because oxytocin, which also increases the expression of Ptgs2, preferentially increases PGF2 [9]. Alternate pathways that would favor selective production of PGE2 would include stimulation of PGE synthase, inhibition of PGF synthase (PGFS), or inhibition of PGE2 9-ketoreductase (9K-PGR). In the last case, down-regulation of a single enzyme would increase PGE2 and lower PGF2. A potential candidate for 9K-PGR activity in the endometrium would be an enzyme isolated from rabbit corpus luteum and found to be the same protein as the previously described 20-HSD found in the rabbit ovary [13,14]. The sequence and functional conservation of this enzyme in mammalians has been demonstrated recently with the isolation of a very similar enzyme from rat corpus luteum [15–17]. Such a 9K-PGR would be a key enzyme in the processes leading to implantation since it regulates, at least in the ovary, both progesterone metabolism and specific prostaglandin production. Because PGF2 is the primary prostaglandin produced by endometrial epithelial cells, we have also studied the regulation of the messenger for PGFS that can convert PGH2 or PGD2 into PGF2 using the published sequence for the messenger of the bovine lung enzyme [18]. Unfortunately, PGE synthase was not investigated in the present study because its cDNA has not been cloned and its sequence was not available [19]. Interestingly, in the present study using a fully characterized bovine endometrial epithelial cell culture, we have amplified uterine fragments corresponding to the ovarian 9K-PGR/20-HSD, cloned it, and effectively shown a down-regulation of the messenger in response to increasing doses of roIFN-. Under the same conditions, we have also shown down-regulation of PGFS mRNA. |
MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Tissue culture plates were purchased from Becton Dickinson (Lincoln Park, NJ). RPMI-1640 and fetal bovine serum were obtained from Gibco BRL (Burlington, ON, Canada). Tracers for PGE2 and PGF2 used in the enzyme immunoassay were purchased from Cayman Chemical Co. (Ann Arbor, MI). All reagents used for the reverse transcription (RT)-polymerase chain reaction (PCR) (MgCl2, dithiothreitol, Moloney murine leukemia virus MLV-RT, Taq polymerase, and respective buffers) and Trizol reagent were purchased from Gibco BRL. Oxytocin (OT) was purchased from Sigma (St. Louis, MO).
Production of Recombinant Ovine IFN- and Antiviral Activity Assay
The roIFN- was provided by Dr. Fuller Bazer. It was produced and purified as described previously by Ott et al. [20] and antiviral activity of IFN- was determined as described by Pontzer et al. [21]. In the present study, the doses used were 0.001, 0.1, and 10 µg/ml. The concentration of roIFN- used is in the physiological range reported for these interferons to produce antiproliferative effects in vitro [22]. Further, it has been shown that secretion of oIFN- increases to about 10 000 ng/h on Day 16 for sheep conceptuses [23] and intrauterine injections of 100 µg/day on Days 11–15 delay luteolysis [20]. The antiviral activity of roIFN- was 1 x 108 U/mg protein.
Isolation of Endometrial Cells and Culture
Bovine uteri were collected at the slaughterhouse within 15 min of death and the physiological status of the tissue was estimated by examination of ovarian morphology [24]. Uteri were transported to the tissue culture laboratory and dissected under a laminar flow hood. In this study, a total of eight early cycle uteri (Days 1–5) were used to generate 8 different cell preparations. Endometrial epithelial cells were cultured in 6-well plates. Medium (RPMI-1640 + 10% FBS-DC depleted of steroids by dextran-charcoal extraction) was changed every 2 days until the cells were used. Confluency of epithelial cells isolated from endometrium in the beginning (Days 1–5) of estrous cycle occurs after 6–7 days and the morphological status of the cells in culture remains stable for at least 15 days.
Experimental Protocol
After the cells reached confluency, the medium was replaced with 2.0 ml of fresh serum-free RPMI-1640 containing different doses of roIFN- (1 ng/ml to 10 µg/ml) or OT (10-9 to 10-5 M). One plate was used for each concentration tested. The IFN- vehicle (10 mM Tris/0.25 M NaCl pH 7.4) or OT vehicle (water) were added to control plates. Cells were then incubated at 37°C in an atmosphere of 5% CO2:95% air for 24 h. For all experiments, at the end of the incubation period, culture medium was recovered for PGs measurement and stored at -20°C until further processing. Cells were recovered for RNA extraction.
RNA Isolation
Total RNA was prepared and extracted using TRIZOL according to manufacturer's instructions. Endometrial cells were directly lysed in 6-well plates with 1 ml of TRIZOL per well. Cell lysates were stored at -80°C and processed within one month. RNA samples were resuspended in water treated with diethylpyrocarbonate (0.05% v:v) and stored at -80°C. Before use, RNA was quantified by measurement of absorbance at 260 nm.
RT-PCR
RT-PCR was used to evaluate 9K-PGR mRNA abundance in response to roIFN-, according to the protocol previously described. Briefly, total RNA samples (400 ng) were reverse transcribed with Moloney murine leukemia virus reverse transcriptase (MMLV-RT, 200 U) and oligo(dT) primers (0.2 µg) in a final volume of 20 µl. A control without MMLV-RT was performed at the same time to ensure absence of any containing genomic DNA. Reaction volumes were then brought to 70 µl. Each reaction was run with 5 µl of RT template or negative control and Taq polymerase (1.5 U) in a final volume of 50 µl. Gene expression was determined using resulting cDNAs by PCR. PCR amplifications were achieved for 40 cycles for 9K-PGR and PGFS and 30 cycles for ß-actin. PCR products were loaded on 0.8% agarose gels and visualized with ethidium bromide. Bands were quantified by image analysis using the AlphaImager 2000 software (Alpha Innothech Corporation, San Leandro, CA). Intensity of each band was normalized to the intensity of corresponding ß-actin band as an internal control.
PCR Primers
Primers sequences were chosen from homologous nucleotide sequences of published rabbit [13] and rat [16] 9K-PGR/20-HSD cDNAs. Amplification was carried out using the antisense downstream sequence 5'-AGC TGG TAG CGA AGG GCA AT-3' and the sense upstream sequence 5'-GAT GCA GGA TTG GCC AAG TC-3'. For PGFS, primers sequences were chosen from a published bovine nucleotide sequence [18]. PGFS sense (S) and antisense (AS) primers were (5'
3'): (S) CGG GCT CTC CAA GAG AAC GGG GT and (AS) GGC CAC TTC ATT CCT GTC CTG GGA. After amplification, 9K-PGR/20-HSD and PGFS cDNAs were cloned in pCR 3.1 plasmid using InvitroGene cloning kit. The cDNA were sequenced by the sequencing service (Laval University, PQ, Canada) using a dideoxy PCR technique. New sense and antisense primers were chosen from 9K-PGR bovine cDNA sequence to increase specificity: (S) CCA AGT CCA TCG GGG TGT and (AS) GCT GCC GTT TTC TTG TGC. As a positive control for each RNA preparation, a ß-actin sequence was also amplified simultaneously in adjacent tubes. A 349-base pair (bp) fragment was amplified using bovine ß-actin cDNA primers (S) 5'-GAG GAT CTT CAT GAG GTA GTC TGT CAG GTC-3' and (AS) 5'-CAA CTG GGA CGA CAT GGA GAA GAT CTG GCA-3'. Expected PCR product lengths were 317 bp for 9K-PGR, 680 bp for PGFS, and 349 bp for ß-actin. All primers were chosen with the aid of the OLIGO 4.01 primer analysis software (National Biosciences, Inc., Plymouth, MN).
Enzyme Immunoassays (EIA) of Prostaglandins
For PGE2 and PGF2 measurements, an EIA was used that utilized acetylcholinesterase-linked PG tracers as described previously [25]. We have used fully characterized rabbit anti-PGE2 [25,26] and sheep anti-PGF2 (Bio Quant, Ann Arbor, MI). The inter- and intraassay coefficients of variation (n = 12) were 16% and 10%, respectively.
Statistical Analysis
Data were analyzed by analysis of variance using Super ANOVA software (Abacus Concepts Inc., Berkeley, CA). Sources of variation included effects due to cell preparations, treatments (roIFN- or OT), and cell preparation and treatment interactions. Individual comparisons of means were made using orthogonal contrasts and Fisher's protected LSD test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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on Prostaglandin Production
Figure 1 demonstrates for the first time both an inhibition and a stimulation of prostaglandin production by roIFN- in epithelial cells. Recombinant oIFN- stimulated significantly PGE2 and PGF2 production at a concentration of 10 µg/ml (P < 0.01) as demonstrated previously [6,8]. However, using a lower dose of roIFN- (1 ng/ml), an inhibition of 25% (P < 0.05) of PGF2 was observed. This situation may involve different intracellular pathways of prostaglandin regulation.
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Cloning of 9K-PG and PGFS
The partial bovine 9K-PGR (Fig. 2) and PGFS (Fig. 3) fragments obtained by RT-PCR were both cloned in pCR 3.1 plasmid and sequenced. The amplified sequence of the bovine 9K-PGR fragment showed homologies of 83% and 78% with rabbit and rat 9K-PGR/20-HSD, respectively. However, using deduced amino acid sequences, homologies of 90% and 88% were found in relation to rabbit and rat amino acid sequences (Fig. 4). For PGFS cDNA sequence, a homology of 90% was found compared to lung PGFS cDNA sequence and 91% with respect to amino acid sequence. Furthermore, a homology of 91% was found between bovine endometrial 9K-PGR and PGFS.
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Expression of 9K-PGR in Different Bovine Tissues
As shown in Figure 5, the abundance of 9K-PGR mRNA was higher in liver compared to kidney, testicle, and ovary. The amount of total cDNA used for the RT-PCR was the same for all tissues tested. Using the same RT-PCR conditions, the relative expression of 9K-PGR mRNA in epithelial cells was equivalent to that observed in liver tissues. The presence of 9K-PGR mRNA was not detected in the oviduct.
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Regulation of 9K-PGR and PGFS mRNA Levels in Response to roIFN- and OT
As illustrated in Figure 6, 9K-PGR gene expression was down-regulated in response to roIFN- (P < 0.05). The effect of roIFN- observed in term of PGFS mRNA gene expression was a reduction (P < 0.05) at low (0.001 µg/ml) and high dose (10 µg/ml). The presence of increasing concentrations OT did not regulate either 9K-PGR or PGFS mRNA gene expression in epithelial cells (Fig. 7).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. This activity has been first identified in 1974 in chicken heart [27], and now several authors have reported its purification from different sources, including human and pig kidney [28], and human brain and liver [29]. This enzyme is, however, better characterized as a carbonyl reductase than a 9K-PGR. A paper published in 1983 already concluded, based on kinetics measurements, that the purified carbonyl reductase and 9K-PGR are not the same enzyme [30], and others have shed significant doubt on the capacity of carbonyl reductase to actually have a physiological 9K-PGR function in vivo [28]. A 9K-PGR activity has also been detected in ovaries and uterus of cyclic and pregnant ewes [31], and it was isolated from ovaries and uterus of different species [32–34]. Thus, if the enzyme responsible for 9K-PGR activity is not the enzyme described above, another enzyme may be involved in this process.
The results in the present study show that roIFN- down-regulates 9K-PGR mRNA gene expression in epithelial cells. This study was conducted to find a possible candidate responsible for the reorientation of prostaglandin production from PGF2 to PGE2 in epithelial cells in response to roIFN- previously described in recent reports by our group [6,8]. In these reports, we have shown that roIFN- up-regulated Ptgs2 mRNA gene expression in both epithelial and stromal cells. These results are supported by work done in vivo in the ovine by Charpigny et al. [35], in which an increase of Ptgs2 protein was observed during early pregnancy. However, the effect of roIFN- on Ptgs2 in epithelial cells could not explain the increase in PGE2 production, since these cells normally produce PGF2 preferentially under unstimulated conditions. The best candidate that could be responsible for this reorientation was an enzyme possessing 9K-PGR activity. The presence of such activity in the uterus has been suggested for several years. The cDNA for this enzyme has been previously cloned in rat and rabbit, and we have used the published sequences to build bovine primers for RT-PCR studies. Another possibility for reorientation of prostaglandins was an action of roIFN- on prostaglandin E isomerase and F synthases. Since the cDNA for the latter enzyme has been cloned in bovine lung, we used its sequence to design primers for RT-PCR. Unfortunately very little is known about the structure of PGE isomerase, and, to our knowledge, there is no mRNA sequence available at the present time [19].
Amazingly, the amino acid sequence of bovine 9K-PGR shows an extremely high level of homology with bovine PGFS, reaching 92%. The homology of these proteins may be related to their common end product PGF2. However, the sequence obtained for bovine endometrial PGFS was slightly different from the lung sequence used to generate the RT-PCR primers. Thus, this enzyme may differ from one tissue to another and may be more selective for its different substrates PGD2 or PGH2 depending on the situation. On the other hand, the bovine amino acid sequence of the 9K-PGR fragment obtained was found to bear 88% and 90% homology with the corresponding enzyme in rat and rabbit, respectively. The results demonstrate that 9K-PGR mRNA is present in various tissues (liver > kidney > testis > ovaries). The relative abundance and the tissue localization of this enzyme are probably related to the specific 20-HSD or 9K-PGR activity of the enzyme. This enzyme seems to be conserved among species and may have a common role in regulating the production of prostaglandin in the periimplantation period.
In the present study, we have confirmed previous results from our laboratory showing an effect of roIFN- mainly on PGE2 accumulation. Others had shown an inhibition of PG production by IFN- at low doses in ovine and bovine endometrial cell cultures [36,37], whereas we reported a significant increase of PG production using higher doses [6,8]. We describe for the first time in the present study a biphasic effect of roIFN-: an inhibition of PGF2 at low dose (1 ng/ml) and a stimulation of PGE2 at higher dose (10 µg/ml). Although the inhibition at low dose was present in the experiments published earlier, the 30% inhibition went by unnoticed because we had expressed our results as percent of control and the inhibition did not appear relevant compared to the 2000–8000% increase then observed in response to bovine and ovine rIFN- [8]. The biphasic response to roIFN- may be due to the presence of high and low affinity IFN receptors. This may be in accordance with the situation in vivo: during early pregnancy, the early conceptus is small and produces low quantities of IFN-, whereas during its elongation and subsequent growth, the concentration of IFN- produced is greater. Another explanation for this biphasic effect could be the binding of roIFN- to different receptors leading to different second messenger pathways and responses. Interestingly, the PGFS mRNA gene expression was down-regulated in response to low dose of roIFN- (0.001 µg/ml), and this may be enough to explain the inhibition of PGF2 observed in this and other studies.
To determine the possible involvement of 9K-PGR enzyme in PGE2 production, RT-PCR studies were carried out using total RNA extracted from epithelial cells treated with increasing doses of roIFN-. In this study, stromal cells have not been used because they preferentially produced PGE2 under unstimulated conditions, and an increase of Ptgs2 could explain by itself the increase in PGE2 production. An increase of Ptgs2 gene expression was observed with a treatment of OT in epithelial cells [9]. Again, an increase of Ptgs2 can explain by itself the increase of PGF2 production, since these cells produce higher amounts of PGF2 at the basal level. The present results demonstrate a down-regulation of 9K-PGR gene expression in response to roIFN- (10 µg/ml). The presence of PGFS mRNA was detected and also down-regulated by roIFN-. This result was obtained at low IFN concentration and is in agreement with work published by Xiao et al. [10,38]. The significant inhibition of both 9K-PGR and PGFS gene expression may be responsible for the increase in the PGE2/PGF2 ratio and accumulation of PGE2. OT had no effect on either PGFS or 9K-PGR mRNA gene expression, which is consistent with a single effect on up-regulation of Ptgs2 gene expression [9].
In conclusion, our results demonstrate that the messenger for a 9K-PGR enzyme is present in bovine endometrial cells and is regulated by roIFN-. It suggests that 9-keto reduction of PGE2 into PGF2 is a possible regulation site for the relative production of PGE2 and PGF2 in epithelial endometrial cells at the time of pregnancy recognition. This hypothesis is supported by the work published by Xiao et al. [38] in which they have shown that following stimulation of epithelial cells with oxytocin, the rate of PGE2 production is increased faster than that of PGF2. On the other hand, at 24 h the rate of production of PGF2 is much higher than that of PGE2. The eventual dual activity of the enzyme that we describe in the present work makes it only more attractive, as progesterone and prostaglandins are key cofactors at the time of recognition of pregnancy. These results also suggest that it will be possible to regulate fine tissue function through the modulation of specific enzymes generating individual prostaglandins.
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ACKNOWLEDGMENTS |
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and Dr. Thomas G. Kennedy for generously donating the PGE2 antiserum for the ELISA technique. We are also grateful to Sophie Parent and Christine Légaré for their helpful discussions. |
FOOTNOTES |
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1 This work has been supported by Natural Sciences and Engineering Research Council of Canada (NSERC) grant #OGPIN030 (M.A.F.) and an NSERC scholarship (E.A.). 
2 Correspondence: M.A. Fortier, Ontogénie et Reproduction, Centre de Recherche du Centre Hospitalier, de l'Université Laval, 2705 Boul. Laurier, Ste-Foy, PQ, Canada G1V 4G2. FAX: 418 654 2765; mafortier{at}crchul.ulaval.ca
3 Current address: Reproductive Biology Unit, Department of Obstetrics & Gynecology and Cellular & Molecular Medicine, University of Ottawa, Loeb Health Research Institute, Ottawa Civic Hospital, Ottawa, ON, Canada K1Y 4E9.
Accepted: September 3, 1999.
Received: November 13, 1998.
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J. K. Pru, B. R. Rueda, K. J. Austin, W. W. Thatcher, A. Guzeloglu, and T. R. Hansen Interferon-Tau Suppresses Prostaglandin F2{{alpha}} Secretion Independently of the Mitogen-Activated Protein Kinase and Nuclear Factor {{kappa}} B Pathways Biol Reprod, March 1, 2001; 64(3): 965 - 973. [Abstract] [Full Text]
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