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RESEARCH |
School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough LE12 5RD, UK and 1 Reproduction, Genes and Development Group, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts AL9 7TA, UK
Correspondence should be addressed to A P F Flint; Email: anthony.flint{at}nottingham.ac.uk
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Introduction |
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The role of PGE2 in activating adenylyl cyclase at implantation has been particularly well defined in species with endometrial decidualization. In mouse, rat, rabbit and man, PGE2 is involved in endometrial angiogenesis (Jabbour & Sales 2004), vasodilatation and vascular permeability (Kennedy 1983), stromal cell prolactin expression (Frank et al. 1994) and decidualization. These processes involve signalling through the PGE2 receptors EP2 and EP4, which are linked to adenylyl cyclase (Fujino et al. 2005) and are expressed by endometrial epithelial and stromal cells.
Although they are less well understood, PGE2 has similar effects in species without decidualization and in which implantation is superficial, such as ruminants. In the bovine uterus, epithelial and stromal cells express EP2 (but not EP4) receptors (Arosh et al. 2003); both cell types synthesize PGE2 (Fortier et al. 1988, Asselin et al. 1996), and PGE synthase concentrations increase with time after ovulation (Arosh et al. 2002). The blastocyst also secretes PGE2 in cattle (Wilson et al. 1992) and sheep (Marcus 1981, Hyland et al. 1982), and PGE2 is luteotrophic on administration to the uterine lumen (Magness et al. 1981). As a result, PGE2 has been suggested to function as a maternal recognition of pregnancy signal in these species. Thus, although all aspects of the involvement of PGE2 and cAMP in early pregnancy have not been demonstrated in all species, they are clearly involved whether or not the endometrium decidualizes.
Genes transcribed in response to cAMP in the endometrial stroma have principally been studied in the context of decidualization (Popovici et al. 2000). Among these are genes coding for a variety of transcription factors, growth factors and compounds involved in angiogenesis, and the decidualization marker prolactin (Christian et al. 2002, Gellerson & Brosens 2003, Yoshino et al. 2003). They also include cyclooxygenase-2 (COX-2; Zhou et al. 1999, Schroer et al. 2002, Wu & Wiltbank 2002), which plays an essential role in the establishment of pregnancy (Reese et al. 2001) by converting arachidonic acid into prostanoids required for implantation (Lim et al. 1999). As COX-2 is induced by cAMP and produces the substrate for PGE synthase, and as PGE2 activates adenylylcyclase, a positive feedback loop has been proposed where by PGE2 induces its own synthesis (Sales et al. 2001, Arosh et al. 2004).
Intracellular concentrations of cAMP are determined not only by its synthesis, but also by its catabolism to 5'-AMP, which is catalysed by a member of the phosphodiesterase (PDE) family specific for cAMP (cAMP-PDE). cAMP-PDE is activated by phosphorylation, notably by protein kinase C (PKC; Tetsuka et al. 1995, Cai & Lee 1996, Geoffroy et al. 1999, Bian et al. 2000). Compounds activating PKC might, therefore, be expected to reduce intracellular levels of cAMP, and so may oppose the action of PGE2 and hinder the establishment of pregnancy.
Arachidonic acid and other polyunsaturated fatty acids are PKC activators (Khan et al. 1995), which may lead to activation of cAMP-PDE. Arachidonic acid is produced in the endometrium at luteolysis through cytosolic phospholipase A2 (Lee & Silvia 1994, Burns et al. 2000) and in response to activation of phospholipase C following oxytocin receptor (OTR) occupancy (Flint et al. 1986), and has been proposed to act as a paracrine messenger between the endometrial epithelium and stroma at luteolysis (Sheldrick et al. 2006), as in other reproductive tissues (Cooke et al. 1991). Both OTR concentrations and PKC activity were higher in the non-pregnant horns of unilaterally pregnant ewes on day 16 after oestrus than they were in the pregnant horns of the same sheep (Abayasekara et al. 1995), which is consistent with oxytocin-induced production of PKC activators such as diacylglycerol or arachidonic acid. Control of arachidonic acid release from cells through endocrine or immune stimulation is consistent with paracrine or autocrine functions of fatty acids in other tissues (Zheng et al. 1999, Ronco et al. 2002).
In addition to PGE2, COX-2 also provides the substrate for PGF2
production, the ratio PGE2:PGF2 produced being determined by the relative activities of PGE and PGF synthases. Through PGF2 (FP) receptor activation of phospholipase C, PGF2 also induces PKC (Abayasekara et al. 1993), and therefore, metabolites of arachidonic acid may also affect cAMP-PDE activity.
The experiments described here were designed to determine whether arachidonic acid interferes with cAMP signalling in bovine endometrial stromal cells, by measuring cAMP in cells in culture and using COX-2 levels as an indicator of the cellular response to cAMP signalling.
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Materials and Methods |
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Cell culture
Bovine uterine stromal (BST) cells isolated from one uterine horn of a non-pregnant cyclic cow on day 16 post-oestrus (Flint et al. 2002) were maintained in Dulbecco’s modified Eagles medium (DMEM; Sigma) with 1% antibiotic–antimycotic (ABAM; Sigma) and 10% foetal bovine serum at 37 ° C, 95% humidity and 5% CO2. They were passaged at intervals of 3–4 days when about 80% confluent. The stromal (as opposed to epithelial) phenotype of the cells was confirmed by their prostanoid secretion pattern (PGE2 > PGF2 ; Asselin et al. 1996). For experimental treatments, cells were plated into multiwell plates 48–72 h before use. The medium was changed to DMEM containing 10% dextran-coated charcoal-stripped foetal bovine serum and 1% ABAM at the time of addition of test compounds. For intracellular cAMP measurements, BST cells were seeded into six-well plates at a density of 106 cells/well; for immunoblotting cells were plated in 24-well plates at a density of 2–4 x 105 cells/well.
Immunoblotting
Lysates (10 µ g protein) were subjected to electrophoresis using 10% acrylamide gels (5% stacking gels) before electroblotting onto Optitran BA-s 83 membrane (Schleicher and Schuell, Anderman and Company, Kingston-upon-Thames, UK) in 25 mmol/l Tris (pH 8.3) containing 148 mmol/l glycine and 20% (v/v) methanol. For detection of COX-2, membranes were probed with COX-2 antibody (C-20; SC 1745, Santa Cruz, obtained through Autogen Bioclear, Calne, UK; 1:250 dilution in phosphate-buffered saline containing 1% w/v Marvel milk powder and 0.5% v/v Tween 20). The second antibody was donkey anti-goat IgG–horseradish peroxidase (SC 2020; Santa Cruz; 1:11 000 dilution in phosphate-buffered saline containing 3% w/v Marvel, 0.5% v/v Tween 20), and visualization was by ECL (Amersham) using Kodak BioMax Light film. Colour Markers (29–205 kD; Sigma) were used to identify molecular weights of proteins, and band intensities were quantified using Kodak 1D digital image analysis software.
3' ,5'-cAMP assay
After incubation with different treatments, the medium was removed and the cells were treated with 0.1 mmol/l HCl to inhibit PDE activity and lysed with 0.1% v/v Triton X-100 for 10 min. The cAMP released was measured using either cAMP (low pH) immunoassay kits or the Parameter cAMP assay system (both from R&D Systems, Abingdon, UK) according to manufacturer’s guidelines. Protein contents of lysates were measured to confirm that the wells contained equal numbers of cells; since this was consistently the case, cAMP concentrations were expressed as pmol cAMP/well.
Protein assay
Protein concentrations were measured in cell lysates by the BCA method (Perbio, Cramlingham, UK).
Experimental design and analysis
Experiments involved treatments carried out with at least three replicates (for cAMP measurement) or four replicates (for immunoblotting). All experiments were performed at least twice. To account for differences in band intensity between immunoblots, all blots included two control samples and all experimental treatments were related to the control bands. Statistical analysis of treatment effects was performed by analysis of variance using Genstat, with treatment and experiment identifier as factors. Where significant (P < 0.05) effects were detected, individual means were tested by Student’s t-test. Values are given as means ± S.E.M., and in the figures, bars with different letters are significantly different.
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). None of the treatments affected cell protein concentration.
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, the increase in cAMP observed when cells were treated with PGE2 was reduced by addition of arachidonic acid. Separate dose–response experiments showed that the concentration of arachidonic acid required to cause this effect was in the range of µ mol/l (Fig. 2b).
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). Furthermore, the inhibitory effect of arachidonic acid on the PGE2-induced rise in cAMP level was blocked in cells cultured with the PKC inhibitor, RO318425 (Fig. 3b), and also by prolonged exposure of cells to 4ß-PMA, which downregulates PKC (Akita et al. 1990, Kiley et al. 1990; Fig. 3c).
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). Identical effects were observed with 1 mmol/l IBMX (data not shown).
Effect of arachidonic acid on cAMP-induced COX-2 expression
To confirm that the effect of arachidonic acid on PDE was reflected in a cellular response to cAMP, COX-2 was measured by immunoblotting in cells treated with PGE2 or dibutyryl cAMP with and without arachidonic acid. As anticipated (see Introduction), dibutyryl cAMP added alone increased COX-2 protein levels (Fig. 4a), and PGE2 caused the same response (Fig. 4c). As expected on the basis of the activation of PDE, the increase in COX-2 level due to dibutyryl cAMP or PGE2 was blocked by arachidonic acid. A similar observation was made with forskolin (1 mmol/l for 6 h), which increased COX-2 levels by 46% when added alone and by 7% when added with arachidonic acid (data not shown).
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Discussion |
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Activation of cAMP-dependent PDE by PKC is well known in other cell types, from studies of whole tissues (hamster heart, Lee et al. 1994; rat renal medullary collecting tubule, Tetsuka et al. 1995), intact cells (luteinizing human granulosa cells, Michael & Webley 1991; rat cardiac myocytes, Bian et al. 2000) and subcellular fractions (liver Golgi–endosomal fraction; Geoffroy et al. 1999). It occurs through a series of phosphorylation steps involving mitogen-activated protein kinase and PKA (Houslay & Adams 2003). There are many isoforms of PDE, as well as the kinases involved in this process, and it is not known which isoforms are present, or functional, in the bovine endometrium.
To confirm that the inhibitory effect of arachidonic acid on the cAMP pathway was reflected at the cell protein level, we measured concentrations of COX-2 in cells treated with the cell membrane-permeable cAMP analogue, dibutyryl cAMP. COX-2 is induced in the uterus by cAMP (Arosh et al. 2004) and is therefore an appropriate marker for effects exerted through this second messenger pathway. In these experiments, arachidonic acid blocked or reduced the effect of dibutyryl cAMP. This is consistent with the activation of PDE since dibutyryl cAMP is sequentially hydrolysed, once inside the cell, to monobutyryl cAMP and cAMP. The cAMP generated in this way then activates PKA. Therefore, increased cAMP-PDE activity would be expected to prevent PKA activation through removal of cAMP derived from dibutyryl cAMP and, hence, to block COX-2 accumulation. Identical effects were observed with PGE2 (Fig. 4c) and forskolin, both of which activate adenylyl cyclase.
It was not our aim to identify the mechanisms by which COX-2 levels were affected, but to use COX-2 as an indicator of a cellular response, and therefore, we cannot differentiate between increased gene expression and reduced turnover of COX-2 transcripts or protein. However, COX-2 is under the transcriptional control of CREB through a well-recognized cAMP response element in the gene promoter (Zhou et al. 1999, Wu & Wiltbank 2002, Schroer et al. 2002). Therefore, it is probable that the increased COX-2 level in response to dibutyryl cAMP reflected increased transcription.
It is unlikely that the effect observed here is specific to arachidonic acid, as PKC is activated by a wide range of polyunsaturated fatty acids (Shinomura et al. 1991, Khan et al. 1995). In practice, the fatty acids involved will probably reflect the composition of the phospholipids from which they are derived. As shown by Elmes et al.(2004), arachidonic acid is present at a higher concentration than any other polyunsaturated fatty acid (PUFA) in phosphatidylcholine and phosphatidylethanolamine in the endometrium in ewes, and it is likely that the same applies in cattle. All the other six unsaturated fatty acids present are effective activators of PKC.
Endogenous synthesis of PGE2 by the cells was unlikely to be a factor in the present investigation, as the culture media were changed immediately before test substances were added, hence removing prostanoids accumulated before the experimental period. Rates of production of PGE2 by BST cells in the presence of 50 µ mol/l arachidonic acid were ~20 pmol/mg protein per min (ELR Sheldrick unpublished observations), which with 0.15 mg cell protein per well would be expected to produce a concentration of 6 nmol/l in 5 ml medium after 20 min incubation. This is ~0.2% of the concentration of PGE2 used to activate adenylyl cyclase (3 µ mol/l), and would not be reached until the end of the 20 min incubation with test substances. Conversion of exogenous arachidonic acid to PGE2 clearly did not prevent the inhibitory effect of arachidonic acid, presumably because culture times after addition of test substances were short.
A similar argument suggests that the effect of arachidonic acid was not likely to have resulted from the conversion to PGF2 . The rate of synthesis of PGF2 in the presence of arachidonic acid was ~1/100 that of PGE2, giving a concentration of 0.06 nmol/l after 20 min. Although the stromal cells used here express the FP receptor (ELR Sheldrick unpublished observations), this concentration of PGF2 is 0.006% of that required to activate phospholipase C in other cell types (Abayasekara et al. 1993).
In addition to their effects on PDE, arachidonic acid and other polyunsaturated fatty acids have both activatory and inhibitory actions on adenylyl cyclase, depending upon the adenylyl cyclase isoform and G proteins expressed in target cells. For instance in cells expressing the G protein Gz (a Gi isoform), such as neuronal cells and platelets, arachidonic acid inactivates Gz, leading to adenylyl cyclase activation (Glick et al. 1996). In contrast, in brain cell membrane preparations, arachidonic acid inhibits adenylyl cyclase by a direct interaction with the catalytic subunit (Nakamura et al. 2001). Arachidonic acid may also affect adenylyl cyclase activity through phosphorylation via PKC; in cells expressing type V adenylyl cyclase, phosphorylation by PKC is activatory (Kawabe et al. 1994), whereas in cells expressing type VI adenylyl cyclase, it is inhibitory (Lin et al. 2002). Therefore, the possibility exists that PUFA cause other actions through modulation of the cAMP/protein kinase pathway. Effects such as these did not appear to be important in the present experiments, where there was no change in basal cAMP concentration with arachidonic acid alone. However, the cells were exposed to arachidonic acid for a short time (20 min), and it is not possible to rule out an effect with a slower onset.
The concentration of arachidonic acid used in these experiments (50 µ mol/l) was consistent with the concentration required to activate purified PKC (20–50 µ mol/l; Shinomura et al. 1991). It is probably within the physiological range in the cells in terms of the intracellular level reached during the culture period. The concentration of free arachidonic acid in bovine stroma has not been reported, but can be inferred from the Km of enzymes for which it is a substrate (for instance, COX-2, ~5 µ mol/l; Smith et al. 1996) and the concentration of arachidonic acid-containing phospholipids (~800 nmol/g, i.e. 800 µ mol/l on the basis of 1 ml/g; Elmes et al. 2004). On the other hand, the intracellular concentration of arachidonic acid is unlikely to have reached 50 µ mol/l in the short time for which the cells were exposed to it (20 min), since arachidonic acid was added to medium containing charcoal-stripped serum, which would not prevent it gaining access to the cells, but might be expected to bind arachidonic acid avidly, reducing its availability.
In the endometrial stromal cells used here, arachidonic acid antagonized the stimulatory effect of dibutyryl cAMP or PGE2 at the level of cell protein, as shown by measuring COX-2 levels (Fig. 4). This is consistent with the induction of PDE by arachidonic acid and confirms that the effect on cAMP level was reflected in protein synthesis. The results also show that arachidonic acid has both stimulatory and inhibitory effects on COX-2, since it increases COX-2 levels in bovine endometrial epithelial cells when added alone (Parent et al. 2003). These effects have different time courses, in that the action through PDE shown here is rapid (within 10 min), while the rise in COX-2 demonstrated by Parent et al.(2003) peaks at 6 h. The explanation for these apparently contradictory responses may lie in the promiscuity of the COX-2 promoter, which is sensitive to many transcription factors. Their reconciliation at a molecular level must await further understanding of the crosstalk between the second messenger pathways involved.
Events leading to PG production in bovine endometrial tissues are temporally and spatially separated. Beginning at about day 10 after conception, the conceptus secretes PGE2, which initiates a positive feedback loop in the stroma whereby cAMP production leads to COX-2 induction and further production of PGE2. After day 15, in the event that conceptus interferon-
(IFN- ) secretion is absent or insufficient, the OTR is expressed in the epithelium, leading to episodes of PGF2 secretion, which result in luteolysis and a further chance to ovulate. Spatial separation arises because the epithelium expresses the OTR earlier than the stroma and is the principal source of PGF2 , whereas the stroma does not express the OTR until oestrus, and produces principally PGE2 (Asselin et al. 1996, Robinson et al. 1999). Expression of COX-2 in the epithelium is increased both by oxytocin in the non-pregnant animal (Parent et al. 2003) and by IFN- in pregnancy (Emond et al. 2004). Interferons also activate phospholipase A2 (Hannigan & Williams 1991), which would be expected to increase the availability of arachidonic acid to COX-2. In both cases, these effects lead to increased secretion of PGF2 . In the non-pregnant animal, the secretion of PGF2 is pulsatile, as a result of a positive feedback loop stimulating further luteal secretion of oxytocin (Flint & Sheldrick 1982). In pregnancy, IFN- leads to increased secretion of PGF2 (Peterson et al. 1976, Payne & Lamming 1994), but without pulses. Secretion of PGF2 is required to be pulsatile in order to cause luteolysis, and as a result, oxytocin causes luteolysis but IFN- does not. Indeed, a prolonged and sustained rise in PGF2 in response to IFN- may lead to luteal refractoriness through downregulation of PKC (Abayasekara et al. 1993), and hence act as an antiluteolysin.
The physiological significance of the inhibitory action of arachidonic acid on the adenylyl cyclase pathway presumably resides in inhibitory effects not only on COX-2 and the response to PGE2, but also on other compounds acting through cAMP. The effect of arachidonic acid on PGE2-induced cAMP accumulation observed here would be expected to prevent responses to agents elevating cAMP levels such as relaxin, activin, luteinizing hormone and corticotrophin-releasing hormone (Bartscha & Ivell 2004, Tierney & Giudice 2004). In this context, arachidonic acid may be viewed as a component of a complex of luteolytic signals maintaining the endometrium in a non-pregnant state characterized by a low level of cAMP, absence of decidualization, vasodilatation and endometrial angiogenesis, and lack of support for the progesterone receptor (Gellerson & Brosens 2003). These interactions are summarized for ruminants in Fig. 5. The outcome of a reduction in endometrial cAMP level may therefore be to ensure blockade of signals associated with pregnancy, such as increased stromal COX-2 and PGE2 production, in the event IFN- production is low and pregnancy is likely to fail. This would impart the selection advantage of securing resumption of cyclicity and a further chance of conception at the earliest opportunity.
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Received 18 September 2006
First decision 16 October 2006
Revised manuscript received 12 January 2007
Accepted 25 January 2007
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References |
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