Prostaglandin biosynthesis

Prostaglandins are notorious mediators of pain, fever, inflammation and hypertension, and their production has been a target for pharmacological therapy with non steroidal anti-inflammatory drugs (NSAIDs) for more than a century. PGs are produced by all nucleated cells of the body and act locally in a paracrine or autocrine fashion. The first limiting step in the generation of eicosanoids is the liberation of arachidonic acid from membrane phospholipids by phospholipases and the most relevant for the production of PGs from arachidonic acid is cPLA2a (1). Arachidonate can then be sequentially transformed into leukotrienes, not covered in the present review, and different active prostanoids (Fig. 1). PGH2, the common precursor of all PGs is generated from arachidonic acid (AA) by prostaglandin synthase (PGHS or COX). There are two isoforms encoded by distinct genes (2) the constitutive isoform, COX-1, is widely expressed in a variety of tissues and cells, whereas the inducible form, COX-2, is regulated by factors such as: cytokines or tumour promoters (3). A splice variant of COX-1 was referred to as COX-3, but its contribution to physiological or pathological conditions remains speculative. COX-1 is constitutively expressed in most tissues and responsible for housekeeping functions and immediate response to levels of AA above 10 µM. COX-2 is regulated by factors such as cytokines or tumour promoters and supports sustained production of PGs from relatively low levels of AA (below 2.5 µM) (4). PGH2 produced by COXs is the common precursor for generation of primary PGs including PGE2, PGF2, PGD2, PGI2 and TxA2 by cell-specific isomerases and synthases such as PGES, PGFS, PGDS, PGIS and TXAS, respectively.

Fig. 1. Prostaglandin biosynthesis pathways. Cytosolic PLA2 (PLA2G4) releases arachidonic acid (AA) from membrane phospholipids and COX enzymes (PTGS1, PTGS2) convert it to PGG2 and PGH2, the common precursor for all PGs. PGH2 is then converted into one of the active PG by specific terminal synthases such as PGE synthases (PTGES, PTGES2, PTGES3), PGF synthases (AKR1B1, AKR1C3), PGD synthase (PGDS), PGI synthase (PGIS) and Thromboxane synthase (TXA1S). PGE2 and PGF2a are inactivated into PGEM and PGFM by HPGD (15-PGDH), PGD2 converts spontaneously into active PGJ2 whereas unstable PGI2 and TXA2 convert into inactive 6K-PGF1 and TXB2.

The physiological importance of prostaglandins has been confirmed in the mouse where targeted disruption of COX-1 (5) or COX-2 genes (6) resulted in severe nephropathy or reduced reproductive efficiency in homozygous null mice. In fact, female COX-2 null mice suffered from multiple failures in reproductive processes (7). Other studies have shown that COX-2 expressed in COX-1 deficient mice was able to compensate at least partly (8). COX-1 -/- and COX-2-/- double knockouts induced death early after birth of the pups suggesting that PGs might be more important for survival than initially anticipated (9, 10).

Pharmacological control of PG biosynthesis is more than a century old. Indeed, Aspirin (ASA) was the first non steroidal anti-inflammatory drug (NSAID) commercialized. ASA shares with newer drugs like ibuprophen (ADVIL) the ability to inhibit non-selectively COX-1 and COX-2 activities (11). More recently, new inhibitors like NS-398 and SC-560 have been shown to specifically block either COX-2 (12) or COX-1 (13) opening the field for the development of more specific NSAIDs such as CELEBREX and VIOXX. However, severe side effects of COX-2 inhibition such as heart failure (14) and infertility (15) lead to the widely publicized withdrawal of VIOXX from the market. Total blockade of all PGs by NSAIDs provides a quick relieve of symptoms but unfortunately deprives from a physiological cure (16). In this respect, targeted action at the level of terminal synthases such as PGES and PGFS responsible for the selective production of PGE2 and PGF2 appears as promising and important to explore (17).

Prostaglandin signal transduction

The different prostaglandins exert a wide array of different or even opposite actions mediated by specific receptors sometimes taking multiple isoforms for a single prostaglandin (Fig. 2) (18, 19). PGs represent a class of local regulators with complementary or opposing actions depending on the type of PG or the receptor signalling their action. PGF2 acts through FP receptors coupled to Gq, PLC and Ca++ release whereas PGE2 acts through 4 classes of receptors, EP1 coupled to Gi and calcium channels, EP2 and EP4 coupled to Gs and cAMP generation, and EP3 for which there are 8 splice variants in the human coupled principally to the inhibitory Gi system (20). Considerable efforts were made to develop selective agonists and antagonists of PG receptors over the last 30 years, but most treatments aiming at controlling PG action are still based on systemic COX inhibition (21).

Fig. 2. Prostaglandin signalling pathways. Immediately upon biosynthesis, PGs exit the site of production passively or through constitutively expressed facilitated transport (MRP4) and either bind to specific membrane receptors in an autocrine or paracrine manner. PGE2 and PGF2 can travel across successive cell layers through PGT or enter target cells to act on nuclear receptors or be inactivated by 15-PGDH. The membrane DP, EP1-4, FP, IP and TP receptors are coupled to diverse G protein and second messengers as illustrated. PGJ2, the spontaneous active metabolite of PGD2 is the physiological ligand for the nuclear receptor PPAR whereas PGI2 binds to PPAR.

Peroxisome Proliferators-Activated Receptors (PPAR , , ) have been proposed as nuclear receptors for PGD2 and PGI2 (22). Recently EP2 and EP4 have been identified in the nuclear envelope suggesting the presence of functional nuclear receptors for PGE2 (23). However, limited information is available on the putative actions of nuclear receptors.

Prostaglandins and reproduction

Apart from sex steroids, prostaglandins are probably the most important regulators of female reproductive function (ovulation, uterine receptivity, implantation and parturition) and associated pathologies (24). Reproductive tissues express different classes of prostaglandin receptors (25). Among the different PGs, PGE2 and PGF2 are the main prostanoids produced in the human (26, 27) and bovine (28) endometrium. The physiological importance of PGs in reproduction has been confirmed in the mouse where targeted disruption of COX-1 or COX-2 genes reduced reproductive efficiency (5-7). Null mutation for cPLA2 a PG biosynthesis enzyme upstream of COX-2, also leads to an infertile phenotype (29). At the receptor level, deletion of the PGF2 receptor (FP) showed that it is necessary for parturition in the mouse (30) whereas EP2 receptors null mutants exhibit ovulation and peri-implantation problems (31, 32).

In the reproductive system, PGF2 and PGE2 often exhibit opposite actions (Fig. 3) (33). The endometrial release of PGF2 in response to oxytocin is the initial signal triggering luteolysis in animals and ovarian PGF2 contributes to the luteolytic process in primates including humans (34). In presence of a viable embryo, the default luteolytic signal is counteracted by an antiluteolytic or a luteotrophic signal or a combination of both to maintain the production of progesterone. PGF2 is also a potent constrictor of the myometrium and uterine blood vessels (21). By contrast, PGE2 is vasodilator able to exert a strong luteotrophic action in human (35). Prostaglandins, especially PGE2, are produced by early embryos and we have found that PGES (36) is increased at the time of maximal uterine receptivity. Similar observations in the mouse, suggest that PGE2 contribution to this process is well conserved among species (37, 38). At the time of implantation or recognition of pregnancy, PGE2 induces a local alteration in growth factors secretion and nutrients and increases vascular permeability (39, 40). PGE2 is a potent immunomodulator mediating the local maturation/differentiation processes (41) and inhibiting the lytic activities of both NK and lymphokine activated killer (LAK) cells (42) around the time of implantation in the endometrium. Consistent with the roles attributed to PGs, the treatment of pregnant females with NSAIDs inhibits implantation or at the very least reduces pregnancy rates (15). In humans, PGs interact with cytokines and PRL to regulate decidualization and with angiogenic and coagulation factors to regulate menstruation (43). During the menstrual cycle, the concentration of PGF2 is apparently higher than PGE2 during the secretory phase whereas levels of both PGs are low during the proliferative phase. The concentrations of PGE2 remain low whereas PGF2 goes higher during menstruation and lower during the implantation window (44). Our data and a recent reviews concur to state that across species, PGF2 and PGE2 are universally important in the regulation of endometrial function (43, 45).

Fig. 3. Prostaglandins production and action in the endometrium. PGE2 and PGF2 are the primary PGs produced in the endometrium of all species studied so far. While endometrial cells produce both, epithelial cells preferentially release PGF2 and stromal cells PGE2. PGs can then act on the neighbouring cells to regulate endometrial function or travel across cells and tissues to reach the ovary and exert a luteolytic or luteotrophic effect to regulate progesterone production. When native PGs enter the vascular system, PGF2 exerts a TXA2 like contractile response whereas PGE2 induces a prostacyclin-like relaxation response. Native PGs are catabolised in the lung and metabolites cleared in the kidney.

SELECTIVE PGF2 AND PGE2 RELEASE
It is widely acknowledged that PGs play a critical role in reproductive processes. The expression of rate limiting enzymes such as phospholipase A2 (cPLA2) and prostaglandin synthases 1 and 2 (PGHS-1/-2) also called cyclooxygenases (COX) regulates the rate of production of PGs as a group, but other mechanisms are needed for selective production of specific PGs. It is increasingly evident that the physiological action of PGs is regulated at multiple levels not only quantitatively, but also qualitatively by selective biosynthesis, expression of specific receptor subtypes, and specialized transport across cell membranes and compartments.

Very little has been done to identify the biosynthetic pathways leading to the formation of specific prostaglandins. Initially it was thought that a single type of PG was produced by distinct subsets of cells (46, 47). Our results with primary cultures now confirmed with clonal cell lines (48) demonstrated that endometrial cells can produce more than one PG. Therefore, conditions leading to the generation of a particular PG vary and must be set within individual cells.

Selective PGF2 production

PGF2 can be produced from three distinct pathways (Fig. 1) but most likely through reduction of PGH2 by 9, 11-endoperoxyde reduction referred to as PGFS activity. Several PGFS have been identified; three were isolated in the bovine: lung type prostaglandin F synthase (PGFS1) (49), lung type PGFS found in liver (PGFS2) (50) and liver type PGFS, also called dihydrodiol dehydrogenase 3 (DDBX) (51, 52). Others were identified respectively in human (AKR1C3) (53), sheep (54), Trypanosoma brucei (a protozoa) (55) and recently the porcine endometrium (56). All recognised mammal PGFSs belong to the aldoketoreductase 1C family, and are generally associated with hydroxysteroid dehydrogenase (HSD) activity. In the bovine endometrium we have shown that none of the presumed functional PGFS was expressed under any condition while we identified AKR1B5, an old enzyme with a new function, as a functional PGFS (28). We have studied the characteristics of various PGFS isoforms in relation with PGF2 production (Fig. 4). We found that aldoketoreductase 1B5 (AKR1B5) was the most likely PGFS involved in the production of PGF2 in bovine endometrium at the time of luteolysis (28). Interestingly, with its 20HSD activity, this enzyme can also inactivate progesterone, another factor regulating endometrial function (Fig. 5). The human equivalent of the bovine AKR1B5 is AKR1B1 belonging to the AKR superfamily composed of 140 members divided into 15 families (57). AKR1B1 is one of 13 human AKRs catalyzing reactions on a broad and overlapping list of substrates making it difficult to find natural substrates and specific functions for any of these enzymes. AKR1B1 also known as the aldose reductase is highly expressed in the placenta for glucose metabolism and in the eye and kidney for osmotic regulation (58). We have accumulated several lines of evidence supporting the hypothesis that AKR1B1 is a functional PGFS in the human endometrium, but we are currently the only group exploring this avenue. We have studied AKR1B1 and demonstrated its association with PGF2 production in human endometrial cell lines (48) and in decidualized stromal cells (59). In a cell free system, purified AKR1B1 recombinant protein is able to produce PGF2 from PGH2. Endometrial cell lines transiently transfected with an expression vector coding for AKR1B1 exhibit increased ability to release PGF2. In contrast, when AKR1B1 expression is knockdown with specific siRNAs, PGF2 production is decreased. We have found that the other potential PGF synthase (AKR1C3) is also expressed in endometrial cell cultures but its contribution to PGF2 production remains to be determined.

Fig. 4. Selective production of PGE2 and PGF2. Following release of arachidonic acid (AA) from plasma membrane phospholipids primarily through cytosolic Phospholipase A2 (cPLA2), conversion into PGH2, the common precursor for all PGs, occurs through PGH synthase or COX, for which there are two isoforms COX-1 and COX-2 encoded by 2 genes, PTGS1 and PTGS2. PGH2 can then be converted into active PG by terminal synthases. We present two putative PGFS, AKR1B1 and AKR1C3 for PGF2 and three PGES, mPGES-1, mPGES-2 and cPGES for PGE2.

Fig. 5 . Multiple enzyme activities of AKR1B1. AKR1B1 was first associated with conversion of glucose into sorbitol and accordingly named aldose reductase. The corresponding bovine AKR1B5 was first identified as a progesterone processing enzyme with 20 HSD activity. While both AKR1B5 and AKR1B1 express the latter activities, we have demonstrated that in both species, the primary activity of these enzymes is PGFS.

Selective PGE2 production

Three forms of PGE synthase (PGES) have been characterized so far (Fig. 4). Microsomal PGES-1 (mPGES-1) was the first identified and reported as inducible by agents such as cytokines and LPS (60). This enzyme is often coupled with COX-2 for delayed and sustained production of PGE2 (61). We have described previously the regulation of mPGES-1 expression during the bovine oestrous cycle and its association with COX-2 (36). A cytosolic PGES (cPGES), identical to p23, a ubiquitous chaperone protein weakly bound to the steroid hormone receptor/hsp90 complex, was characterized and found coupled to COX-1 for immediate production of PGE2 (62). Enzymatic activity from a third PGES, microsomal PGES-2 (mPGES-2), was purified from bovine heart and cloning of homologous human and monkey sequences was done (63). This PGES is associated with both isoforms of COX with a slight preference for COX-2 (64) and we have documented its expression in the endometrium during the oestrous cycle (65) while we have cloned and sequenced the other two PGES from the macaque endometrium (66). In the bovine endometrium, all three PGES are expressed during the oestrous cycle with mPGES-1 dominating around ovulation. In cell cultures only mPGES-1 was found to increase in parallel with COX-2 when PGE2 production was stimulated with various factors (65).

In the human endometrium, the three known PGES, mPGES-1, mPGES-2 and cPGES are expressed during the menstrual cycle together with COX-1 and COX-2. At the mRNA level, mPGES-1 is expressed maximally during menses, mPGES-2 during the secretory phase and cPGES is expressed at a constant level. We have shown that mPGES-1 protein expression was stimulated following decidualization of stromal cells in vitro (59). In human endometrial cell lines, mPGES-1 mRNA and protein expression are highly stimulated by IL-1ß and associated with PGE2 production (48). Accordingly, knockdown of mPGES-1 with a specific siRNAs decreased mRNA, protein and associated PGE2 production. It is worth noting that mPGES-1 appears to mediate most effects following stimulation of PGE2 production, but although mice with null mutation for this gene are insensitive to LPS and NFB they do not exhibit the fertility problems found for COX-2, EP2 or cPLA2 knockout. Therefore, the mPGES-2 and cPGES are either able to compensate or are solicited as contributors for PGE2 production through an NFB independent mechanism (67).

Physical association (team up) of PG biosynthetic enzymes

Biosynthesis of a specific PG requires simultaneous expression of the different members of the biosynthetic cascade (Fig. 1, Fig. 4). However, this does not rule out simultaneous expression of more than one terminal synthase. Therefore selective production may also involve functional association (compartmentalization) of complementary enzymes. This may include linking, association around scaffold proteins or grouping on a common structure. To date, no specific scaffolds involving PG biosynthesis have been identified. Terminal synthases are necessary to produce a specific PG but spatiotemporal association with upstream phospholipase and COXs is necessary to access the rate limiting precursors AA and PGH2. Functional associations between terminal synthases and upstream COXs have been described almost exclusively for the different PGES using transfected cell lines. Microsomal PGES-1 is often coupled with COX-2 for delayed and sustained production of PGE2 initiated by cytokines or LPS through an NFB mediated mechanism (61). mPGES-2 is associated with both isoforms of COX with a slight preference for COX-2 (64) and cPGES is coupled to COX-1 for immediate release of PGE2 (62). There is no data available to link any PGFS with upstream enzymes of the PGF2 cascade at the functional or the transcription level (67), but our data suggest functional association of AKR1B1 with COX-2 (48) and potential association with COX-1. A study on AKR1C3 in transfected HEK-293 cells suggested preferential association with COX-1 (68). In bovine epithelial cells PGF2 production is stimulated preferentially by oxytocin through a PLC-PKC mediated pathway (69) and PGE2 with interferon (IFNt) (70) potentially through a NFB mediated mechanism. In contrast, both PGs are increased simultaneously under all conditions tested so far in human endometrial cells (48, 71). There appear to be a trend for preferential stimulation of PGF2 and AKR1B1 in response to IL-1ß in human endometrial cells, but significant increases in PGE2 and mPGES-1 are also observed.

Because the selective production of one PG such as PGE2 requires synchronous expression of at least 3 enzymes and because endometrial remodelling involves coordinate expression of multiple genes favouring cell proliferation and angiogenesis, key regulatory factors are likely to liberate transcription factors acting on a cassette of complementary genes. Some groups working on the involvement of PGs in cancer and inflammation have described important regulation by transcription factors such as TonE/NFAT5 (NFB), NRF-2 and EGR-1, but very little has been done on reproductive tissues or non pathologic conditions such as pregnancy or menstruation. Our results showing a time and dose dependent increase in PGF2 associated with a parallel increase in AKR1B1 mRNA in response to IL-1ß suggested transcriptional regulation of the AKR1B1 gene. Accordingly, we have cloned a 4.5 kb AKR1B1 promoter in the basic pGL3 vector coupled with the luciferase reporter gene. This construct is strongly activated by IL-1ß. Progressive 5'deletions allowed to identify an IL-1ß sensitive region located at -1177 to -1047. In the mouse AKR1B3 gene, homologous to the human AKR1B1, an Nrf2 binding motif is regulated by the antioxidant response element (ARE) present in the Multiple Stress Response Region (MSRR) (72). We have identified the corresponding putative trans-acting factors TonE/NFAT5, AP1, Nrf2 and NFB in the AKR1B1 promoter. In the mouse, knocking out NFAT5 (TonE) leads to down-regulation of the AKR1B3 gene and poor embryo survival (73), disrupting the Nrf2 gene leads to a normal and fertile phenotype under controlled environment, but extreme susceptibility to oxidative stress, characteristic of PG biosynthesis (74). Interestingly, using constructs coupling different MSRR fragments of the AKR1B1 promoter with the SV40 pGL3-promoter, we have identified two AREs as important factors mediating the effect of IL-1ß, potentially through Nrf2, in human endometrial cells. In addition, mutations in the osmotic response element ORE (TONE) of the same MSSR fragment lead to decreased promoter activity following IL-1ß stimulation. It was reported that NFB was able to bind ORE of the AKR1B1 gene in human liver and lens cells treated with TNFa (75) whereas involvement of Nrf2 was shown in the regulation of TXA2 synthase an important vasoactive PG in platelets (76). Finally, numerous constructs and mouse mutation models used to characterize the NFB system point to genes associated with AA metabolism as important targets (77). As observed for AKR1B1, PGE2 production and mPGES-1 mRNA exhibit a parallel increase in response to IL-1ß suggesting transcriptional regulation of this gene. We have cloned a 4.2 kb promoter of the mPGES-1 gene and progressive deletion constructs showed that the -1059 +52 region conferred IL1B response whereas position -3096 to -2796 is associated with repressive activity. These are the first data describing promoter activity of a relatively long (4.2 kb) fragment for the human mPGES-1 gene. We hypothesize that Egr-1, an inducible zinc finger protein that recognizes the GC-rich consensus DNA sequence 5'-GCG(T/G)GGGCG-3'box present at the proximal promoter region -119/-112 and -108/-101 of the mPGES-1 gene is a functional transcription factor in endometrial cells. The same regions were found essential for the expression the mPGES-1 gene in osteoblasts and macrophage-like cells (78). IL-1ß has also been reported to repress type II collagen gene in a chondrocyte cell line through Egr-1 (79) while it activates the Tissue Factor gene through Sp1 in Hela cells (80). Egr1 k/o mice have an infertile phenotype originating from lack of functional LH thus making it impossible to estimate its contribution on other aspects of endometrial function (81).

The proximal (1kb) promoters of cPLA2 and COX-2 genes contain several regions with putative cis-elements for NFkB (82). In human lens cells, NFB proteins p50 and p65 interact with the ORE (osmotic response element) complex of the AKR1B1 promoter (75) corresponding precisely to the MSRR region mediating the effect of IL-1ß in our endometrial cell lines. We believe that increased PGF2 production in response to IL-1ß in endometrial cells is somewhat related to oxidative stress for which NFB is considered a sensor (83). Interestingly, Egr-1 (also called Zif-268 or Krox-24) which is likely involved in the regulation of mPGES-1 is also identified as an oxidative stress-early inducible transcription factor when human lens epithelial cells are exposed to H2O2 (84). These data suggest that interactions between transcription factors and binding elements on the promoters of PG synthases, and especially ORE and ARE in the case of AKR1B1 and Egr1 for mPGES-1 provide a functional mean to achieve selective production of specific PGs.

Selective output of PGF2 and PGE2, local transport and catabolism

Prostaglandin transport: PGs predominate as charged anions and in spite of their lipid nature, diffuse poorly through plasma membranes. The mechanisms responsible for the transport of newly synthesized PGs out of producing cells, either by simple diffusion (85), or a PG efflux transporter (86), are still in dispute. It has been shown that though anions cross the cell membrane by simple diffusion, the estimated flow rate would be too low for maintaining a biological function. Therefore, passive diffusion of PG into cells appears to be poor and is thought to be mediated by carriers (Fig. 2) such as prostaglandin transporter (PGT) (85). PGT was the first cloned PG transporter (87) and is a 12-transmembrane protein with a broad tissue expression. It is a functional uptake-carrier with high affinity for PGE2, PGF2 and PGD2 (85). PGT mRNA is expressed in reproductive tissues such as testis, ovary, and uterus (87, 88). PGT belongs to the super family of 12-transmembrane Organic Anion Transporting Polypeptide (OATP). It has been proposed that PGT mediates both the efflux of newly synthesised PGs to effect their biological actions through their cell surface receptors, and influx of PGs from the extra cellular milieu for their inactivation or action through specific nuclear receptors. PGT was found to be expressed preferentially in cell membranes of tissues capable of producing more PGs. Interestingly, PGT and cell surface PG receptors have comparable affinities for their substrates (85). Other members of the same transporter family such as CFTR are involved with efflux function and another member, MRP4 (86), has been proposed as a functional efflux carrier for PGs.

Our group has cloned bovine PGT (89) and characterized PGT as a key player in the action of PGs in the bovine reproductive system (89-92). Recently, we have shown the expression of PGT in the human endometrium (93). The co-expression of PGT and PGDH in a single cell type is believed to be associated with PG catabolism (94) whereas expression of PGT alone may favour transport of PGs across adjacent cells and tissues and mediate paracrine action of PGs (90-92). We have found that decidualization influenced the expression of hPGT and the distribution of PGF2 and PGE2 in the intra and extra-cellular compartments (59). We have also studied the expression of different members of the MRP and OATP transporters in the bovine endometrium and found that the former are preferentially expressed during the early part and the latter in the late part of the oestrous cycle. In vitro, the expression of both transporters was found to be modulated in parallel with PG biosynthesis in response to oxytocin and interferon.

PG catabolism: The first step for biological inactivation of PGs is effected by 15-PGDH (95) (96) and further catabolism by 15-13PGR generates the PGF2 and PGE2 metabolites PGFM and PGEM. There are two types of 15-PGDH, but only type I PGDH is associated with peripheral metabolism of PGs. We have found that endometrial 15-PGDH was modulated during the bovine oestrous cycle suggesting that local catabolism could exert a regulatory mechanism in the endometrium. In the mouse, it has been found that in preparation for parturition a peak of PGF2 is associated with an increase of COX-1 and PGF synthase and a decrease of 15-PGDH while cPLA2 and COX-2 are unaffected (97). In studies focusing on neoplasia pathways the COX-2-dependent production of PGE2 is associated with tumorgenesis and this effect is exacerbated when 15-PGDH expression is reduced (98). In parallel, it has been shown that cytokines like IL-1ß or TNF- are able to reduce significantly 15-PGDH activity at the mRNA level and that the ratio of PGFM/ PGF2 is decreased significantly by steroid hormones (progesterone and dexamethasone) in trophoblast cells in culture (99). These results suggest that net PG production is regulated locally by a complex process involving both synthetic and catabolic enzymes. Preliminary results in the human endometrium indicate that the 15-PGDH protein is present in glandular epithelial cells during the early and mid secretory phases. Because treatment with PG biosynthesis blockers (NSAIDs) is efficient to treat many pathological conditions, we may assume that reduced peripheral catabolism may contribute to some of the disorders observed (100).


DIET AND PROSTAGLANDIN PRODUCTION
Free fatty acid composition and PGFna and PGEn production

Prostaglandins are derived from eicosanoic (C20) fatty acids, and the trend to rely increasingly more on sn-6 PUFA yielding series 2 PGs potentially exacerbates adverse inflammatory and cardio-vascular conditions. In humans, the relative proportion of PUFA in body tissues depends on diet composition. In women, increased release of AA before menstruation is at the origin of increased PGF2 and PGE2 production considered responsible for dysmenorrhea (43, 101) and pre-menstrual syndrome (102). Recent circumstantial evidences suggest that altering even slightly (20%) the fat content of diet towards PUFA favouring series 1 or series 3 PGs can have a significant positive impact on health (Fig. 6). The biologically active series 2 prostaglandins are derived from arachidonic acid (AA) yielding the well known PGF2 and PGE2. Series 3 prostaglandins can be formed from eicosapentaenoic acid (EPA, 20:5n-3) the major fish oil omega 3, which gives rise to PGE3 and PGF3. Series 1 prostaglandins are derived from dihomogamma linolenic acid (DGLA, 20:3n-6) which gives rise to PGH1, PGE1 and PGF1. The biological activity of series 1 and 3 PGs vary among species and between tissues. Manipulation of the dietary intake of PUFAs in a variety of species and models was shown to impact on follicular development, ovulation, corpus luteum function, maternal recognition of pregnancy and parturition (100). It has been established that omega-3 can significantly reduce dysmenorrhea and PMS symptoms presumably through a competitive action of prostaglandins of the 3 series (102). The effects were accompanied by alteration of net output of urinary metabolites, but the exact mechanisms behind were not determined. It was reported that series 1 PGs are anti inflammatory, but long significant alteration of PUFA composition toward DGLA is difficult because of intrinsic conversion into AA the precursor of pro-inflammatory series 2 PGs. It must be stressed that even though many reports militate in favour of increased omega 3 consumption in the diet, recovery of full body function following complete deprivation of FFA is optimal with omega 6 FA such as AA (103).

Fig. 6. Effect of dietary fatty acids on PG production. PGs can be generated from a variety of C-20 polyunsaturated fatty acids (PUFA) present in cell membranes in the form of phospholipids. These PUFA are poorly converted in mammals and must therefore be obtained from dietary intake. AA is the most abundant PUFA in the Western diet and is at the origin of the pro-inflammatory series 2 PGs. DGLA leads to the production of anti-inflammatory series 1 PGs whereas EPA, the omega 3 of fish origin leads to series 3 PGs. While there is no clear identification of the mechanisms responsible for the health benefits of omega 3 FFA, alteration in PG biosynthesis and signal transduction is a likely hypothesis.

Prostaglandin, ROS and antioxidants

There is a close association between the pathways generating reactive oxygen species (ROS) and PG biosynthesis. Reactive oxygen species (ROS) are generated by COXs during the process of PGs biosynthesis and can contribute directly to the regulation of reproduction (104) and initiation of menstruation (105). Interestingly, terminal PG synthases, especially aldose reductases can metabolize ROS. We have observed that AKR1B1 is increased by H2O2 whereas known antioxidants like curcumin vitamin E, N-acetyl cysteine and luteolin decreased in vitro PGs production in human endometrial cells treated with IL-1ß.


PROSTAGLANDINS AND HUMAN PATHOLOGIES
Menstrual disorders

Menstrual disorders can affect women at any point in their childbearing years but are most prevalent during adolescence or the years just before menopause when sex hormones are shifting rapidly. The most common and debilitating menstrual disorders are dysmenorrhea or painful menstruation and menorrhagia or heavy menstrual bleeding (43). Locally released prostaglandins are considered as the primary mediators involved in the aberrant conditions and inhibition of their biosynthesis with non specific COX inhibitors (NSAIDs) is the primary therapeutic approach (Fig. 7). Endometrial PGF2 is highest before the onset of menses. Vasoconstriction induced by PGF2 causes ischemia, accumulation of toxic catabolites, tissue necrosis, and desquamation. Myometrial contractility and abdominal discomfort (cramping) associated with menses are also caused by PGF2. Increased concentrations of prostaglandins have been found in the endometrium and menstrual fluid of women who experience dysmenorrhea (106). The pain associated with uterine ischemia induced by PGF2 may be exacerbated by the hyper hyperalgesic effect of PGE2 on nerve terminals (107). The mechanisms behind dysfunctional uterine bleeding are not fully determined but PGs are again identified as important contributing factors. Increased PGE2 relative to PGF2 levels in endometrium and menstrual fluid have been associated with menorrhagia (108), but altered PGI2 and TXA2 in the spiral arteries may also contribute significantly to this condition. In the case of menorrhagia, both NSAIDs and prothrombotic factors are used as therapeutic treatments. A recent review addresses the involvement of COX enzymes and prostaglandins in reproductive tract physiology and pathology (19). That review re-establishes the importance of COX expression in association with PGF2 and PGE2 in reproductive tract carcinoma, menorrhagia, dysmenorrhea and endometriosis through autocrine/paracrine mechanisms. Aberrations in uterine PG release or receptor expression were also demonstrated in association with premature labour (21).

Fig. 7. Integrated views of PG biosynthetic and signalling pathways associated with menstrual disorders. The terminal synthases associated with the production of all PGs have been identified in the endometrium. However, PGE2 and PGF2 are produced in greater quantity and are the only members of the group with the chemical stability and penetration ability to generate the responses characteristic of menstrual disorders. Dysmenorrhea and menorrhagia are both associated with increased production of PGs, the former is preferentially associated with PGF2 inducing ischemia and pain and the latter with PGE2 exhibiting antithrombotic activity and hyperalgesia. The associations between specific biosynthetic enzymes, receptors and their precise sites of expression remain to be determined.

Complications of metabolic disorders

Metabolic disorders result from complex interactions between genetic and environmental factors disturbing the normal immune and endocrine function. In turn, homeostasis is perturbed resulting in obesity, type 2 diabetes (T2D), increased cardiovascular morbidity and infertility. The contribution of prostaglandins (PGs) to the aetiology of metabolic disorders is poorly documented, but recent literature and our findings suggest that PGs may contribute to the development of associated complications. AKR1B1 and the polyol pathway responsible for conversion of glucose into sorbitol (Fig. 5) have been associated with several pathological conditions such as iron overload (109), alcoholic liver disease (110), heart failure (111), myocardial ischemia (112), vascular inflammation (113) and restenosis (114). Diabetes increases AKR1B1 expression and is associated with the impairment of NO-mediated vascular relaxation and decreased NO bioavailability, which may be a causative factor in other complications (115). However, recent studies have shown that AKR1B1 does not process glucose at physiological concentrations but is an excellent catalyst for the reduction of lipid peroxidation-derived aldehydes and their glutathione conjugates (116-121).

Interestingly, both AKR1B1 (122) and PGF2 (123) are increased in association with type 2 diabetes. This finding together with observation that this enzyme is expressed in adipose tissue, heart, skeletal muscle, eye and kidney (open an entire new field of investigation to study the potential contribution of PGF2, its action relative to PGE2 and substrate interaction with steroids, glucose and their regulators in metabolic disorders such as obesity and diabetes. The newly described PGFS activity of AKR1B1 is also highly relevant to the documented association of this enzyme with cardiac (124-126) and cerebral ischemia (113, 127, 128) (Fig. 8).

Fig. 8. PGFS activity and the aetiology of human pathologies. The generation of sorbitol from high levels of glucose observed in diabetes has been proposed as the primary cause of complications in many organs and systems. However, glucose at physiological concentrations is a poor substrate for AKR1B1. The demonstration of PGFS activity of AKR1B1 and increased expression in uterus, brain, heart and kidney in association with different pathologies, provide a strikingly coherent explanation of the effects observed in these organ and systems and warrant in depth investigation.

Inhibitors of the aldose reductase activity of AKR1B1 were developed to correct aberrant responses associated with diabetes, but serious adverse side effects always occurred leading to their early withdrawal.

Table 1. Inhibitory effects and selectivity of some NSAIDs on Cox-1 and Cox-2 activity.

CONCLUSION
We have presented an integrated view of PGE2 and PGF2 biosynthesis, transport and signalling systems in the human and bovine endometrium. The net production of uterine PGs is governed by the anabolic enzymes COX-1, COX-2, PGES, PGFS and the catabolic enzyme PGDH (129) which are well conserved among species. Of particular interest is the identification of AKR1B1 as a functional PGFS. This activity appears as the missing link to understand the origin of diabetes complication affecting multiple tissues and systems and a promising pharmacological target to treat them (Fig. 8).


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