Journal of Clinical Endocrinology & Metabolism
, doi:10.1210/jc.2004-2496
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4244-4248
Copyright © 2005 by The Endocrine Society
Identification of 9
,11ß-Prostaglandin F2 in Human Amniotic Fluid and Characterization of Its Production by Human Gestational Tissues
Murray D. Mitchell,
Maxwell C. Chang,
Tinnakorn Chaiworapongsa,
Hao-Yi Lan,
Rachel J. A. Helliwell,
Roberto Romero and
Timothy A. Sato
Liggins Institute (M.D.M., M.C.C., H.-Y.L., R.J.A.H., T.A.S.), University of Auckland, and National Research Centre for Growth and Development (M.D.M.), 1020 Auckland, New Zealand; and Perinatal Research Branch (T.C., R.R.), National Institute of Child Health and Human Development, Detroit, Michigan 48201
Address all correspondence and requests for reprints to: Professor Murray D. Mitchell, Liggins Institute, University of Auckland, 2-6 Park Avenue, Grafton, Auckland, New Zealand. E-mail: m.mitchell{at}auckland.ac.nz.
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Abstract
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Context: 9
,11ß-Prostaglandin F2 (9,11ß-PGF2) can contract uterine smooth muscle with a potency equal to PGF2. Its presence in the human uterus and production by human gestational tissues is unknown.
Objective: These studies were performed to determine whether the PGD2-derived 9,11ß-PGF2 is both present in human amniotic fluid and synthesized by human gestational tissues and if so, whether labor-related substances could regulate its production.
Results: Detectable concentrations of 9,11ß-PGF2 were found in amniotic fluid samples and appeared to increase in late gestation. All gestational tissues studied synthesized 9,11ß-PGF2, with the placenta having the highest basal production rate, followed by the amnion and then the choriodecidua. IL-1ß and TNF caused concentration-dependent increases in 9,11ß-PGF2 production in human amnion and choriodecidual explants. Moreover, treatment of choriodecidual and placental explants with lipopolysaccharide resulted in a significant increase in 9,11ß-PGF2 production rates, reaching a maximum of 13-fold in the choriodecidua. Studies examining the effects of the addition of exogenous PGD2 strongly indicated that the choriodecidua has significant ability to convert PGD2 to 9,11ß-PGF2, whereas the amnion has little.
Conclusions: These results demonstrate for the first time that 9,11ß-PGF2 is present in human amniotic fluid and that it is produced by human gestational tissues and up-regulated by bacterial cell wall components and proinflammatory cytokines. We suggest that this prostaglandin may play a part in the mechanisms of human labor at term and preterm.
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Introduction
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IT IS WELL established that prostaglandins (PGs) play a critical role in the mechanisms of parturition both at term and preterm (1, 2). PGs of the E and F series have roles in initiating uterine contractions and ripening of the cervix and even membrane rupture, whereas those of the I series and thromboxanes not only may contribute to these mechanisms but also have roles in preeclampsia (3). All act via well-described cell membrane receptors (4). Derivatives of PGJ2 have been shown to have various biological properties in addition to binding to the peroxisome proliferator-activated receptor (PPAR)-
(5, 6). For instance, 15-deoxy
12, 14-prostaglandin J2 (15d-PGJ2) has apoptotic as well as antiinflammatory properties (7, 8), with biphasic concentration responses (9). The J series PGs are derived from PGD2 (10).
PGD2 can also be enzymatically converted to 9,11ß-PGF2 (11), which has been demonstrated to contract uterine smooth muscle, at times with potency equal to that of PGF2a (12, 13). PGD2 has been reported to be produced by the human placenta (14) and be present in amniotic fluid with levels elevated in women in labor (15). We developed the hypothesis that PGD2 and its derivatives may have a more important role in parturition than previously thought (16). A central tenet of this hypothesis is that the relative flow from PGD2 through to PGJ2 derivatives, especially 15d-PGJ2 and through 9,11ß PGF2, predisposes, respectively, toward the maintenance of pregnancy or the rupture of fetal membranes and/or onset of labor. Indeed, PPAR expression has recently been suggested to facilitate the maintenance of pregnancy via dampening of inflammatory mediator release (17). The presence of 15d-PGJ2 (the PPAR ligand) in amniotic fluid of pregnant women has been described (18). Critically, however, there is no evidence of the presence of 9,11ß-PGF2 in human reproductive fluids. Furthermore, there are no descriptions of 9,11ß-PGF2 production by human gestational tissues, and little is known of the regulation of production in any human tissues. Hence, we conducted the present study to establish the physiological presence of this substance in human pregnancy (by detection in amniotic fluid) and its production by and regulation in gestational tissues. Because enhanced cytokine production has been described in several gestational tissues in concert with parturition at term and preterm (19, 20) and a significant proportion of preterm deliveries occur as a consequence of intrauterine infections (21, 22), we have chosen lipopolysaccharide (LPS) and cytokines as the test agents.
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Patients and Methods
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Amniotic fluid and tissues
All procedures involving human placentas and amniotic fluid collection were approved by the ethics committees at the respective institutions; informed patient consent was obtained. Amniotic fluids from patients at term no labor (TNL), term labor (TIL), preterm no labor (PTNL), and preterm labor (PTIL) were obtained. The preterm samples came from groups in which there was no detectable infection. Details of the collection and the characteristics of these amniotic fluid samples have been described previously (23, 24). Pooled duplicate samples of amniotic fluids from eleven individual patients were used due to restricted volumes available.
Explant cultures
Placentas were obtained from women undergoing elective cesarean sections at term after informed consent was obtained. Criteria for the inclusion of the obtained placentas have been previously described (25). The choriodecidua was separated from the amnion and rinsed in PBS to remove residual red blood cells. Placental explants were generated by fine mincing the placental tissues to remove all connective tissue, pooled, and evenly distributed into a 12-well plate. Using a corkborer, 6-mm disks from the intact choriodecidua and amnion were made and incubated as described previously (25).
Reagents
Bovine--globulin and bacterial LPS were purchased from Sigma Chemical Company (St. Louis, MO). PGD2 was purchased from Cayman Chemicals (Ann Arbor, MI). IL-1 was a kind gift of the Immunex Corp. (Seattle, WA), and the TNF was purchased from John Fraser (Department of Molecular Medicine, University of Auckland, Auckland, New Zealand). Media were purchased from Irvine Scientific (Santa Anna, CA). Fetal calf serum was purchased from Life Technologies, Inc. (Grand Island, NY).
Immunoassays
9,11ß-PGF2 and 15d-PGJ2 were measured by sensitive and specific commercially available ELISA kits (Assay Design, Ann Arbor MI). The manufacturer’s specifications and protocols were followed. The 9,11ß-PGF2 assay had a sensitivity of 5 pg/ml and cross-reacted less than 5% with PGD2 and less than 0.1% with PGE2 and PGF2. The 15-d-PGJ2 assay had a sensitivity of 37 pg/ml and cross-reacted less than 5% with PGD2.
Presentation of data
Concentrations of 9,11ß-PGF2 in amniotic fluids are presented as picograms per milliliter. 9,11ß-PGF2 production rates were calculated as picograms per milligram wet weight per 24 h (mean ± SEM). Data are expressed as a percentage of the control value so that the results from multiple experiments (3-4) could be pooled and analyzed collectively. The significance between the means of untreated control explants, compared with the treated ones, was established by ANOVA (P < 0.05 was considered to be significant, designated by asterisk).
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Results
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All amniotic fluid samples studied had concentrations of 9,11ß-PGF2 well within the level of detectability of the assay with mean concentrations elevated in late gestation and term labor (Fig. 1
). Concentrations of 9,11ß-PGF2 in amniotic fluids from patients at TNL, TIL, PTNL, and PTIL were 204, 396, 30, and 10 pg/ml, respectively; all were above the 5 pg/ml sensitivity of the assay. 9,11ß-PGF2 was produced by all tissues studied. Placental explants had the highest basal production of 9,11ß-PGF2 with amnion and choriodecidual rates much lower (Table 1). Placental explants exhibited no response to IL-1ß and TNF (data not shown). Choriodecidual explants had the greatest fold increase in 9,11ß-PGF2 production when stimulated with IL-1ß or TNF (Fig. 2). At the highest concentration of IL-1ß (10 ng/ml), choriodecidual explants had an 8-fold increase in 9,11ß-PGF2 production, compared with a 3-fold increase in the amnion explants. This trend was more apparent when the explants were stimulated with TNF. At the highest two concentrations (50 and 10 ng/ml), TNF induced a 14-fold increase in 9,11ß-PGF2 production, compared with a 1- to 2-fold increase in the amnion explants. However, it should be noted that although the choriodecidual explants had a higher fold increase in 9,11ß-PGF2, the amnion explants had a statistically significant increased 9,11ß-PGF2 production rate at the lowest concentrations of IL-1ß and TNF (0.2 and 2 ng/ml, respectively), which the choriodecidual explants did not.
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TABLE 1. The basal production rates of 9,11ß-PGF2 by human gestational tissues (mean picograms per milligram weight/24 h ± SEM; n = 3 placentas)
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The effects of LPS on 9,11ß-PGF2 production by choriodecidual explants are presented in Fig. 3. A concentration-related increase in 9,11ß-PGF2 production occurred. At all concentrations of LPS tested (0.4–10 µg/ml), there was a statistically significant increase in 9,11ß-PGF2 production by the choriodecidual explants, ranging from a 4-fold increase to a 14-fold increase at the highest concentration of LPS tested. Amnion explants are relatively refractory to LPS (data not shown) as are placental explants. Hence, only one high concentration of LPS (5 µg/ml) was used, and a 3-fold increase in 9,11ß-PGF2 was observed (Fig. 4).
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FIG. 3. Effects of LPS on 9,11ß-PGF2 production by human choriodecidual explants isolated from membranes from patients undergoing elective cesarean sections. Explants were treated with varying concentrations of LPS, and the media were harvested 24 h later. Results initially derived as picograms per milligram wet tissue weight per 24 h are expressed as percentage of control (mean ± SEM, n = 3 placentas). *, P < 0.05 vs. control.
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FIG. 4. Effects of LPS on 9,11ß-PGF2 production by human placental explants isolated from membranes from patients undergoing elective cesarean sections. Explants were treated with 5 µg/ml LPS, and the media were harvested 24 h later. Results initially derived as picograms per milligram wet tissue weight per 24 h are expressed as percentage of control (mean ± SEM, n = 3 placentas). *, P < 0.05 vs. control.
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The addition of 1000 nM of exogenous PGD2 resulted in a dramatic 1400-fold increase in 9,11ß-PGF2 basal production (Fig. 5A). In the presence of LPS (Fig. 5B), there was a 10-fold increase in the production of 9,11ß-PGF2. The addition of PGD2 at the highest concentration (1000 nM) resulted in a further 30-fold increase. There was no such effect on amnion explants when exogenous PGD2 was added in the presence and absence of IL-1ß stimulation (data not shown). Treatment with LPS resulted in a 5-fold increase in 15d-PGJ2 production by choriodecidual explants. Data presented in Fig. 6 demonstrate that the addition of exogenous PGD2 to human choriodecidual explants also results in an increase in 15d-PGJ2 production; however, there was no further effect in the presence of LPS. There was also no effect on the rates of PGE2 production with the addition of exogenous PGD2 (data not shown).
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FIG. 5. Effects of PGD2 addition on 9,11ß-PGF2 production by human choriodecidual explants isolated from membranes from patients undergoing elective cesarean sections. Explants were treated with varying concentrations of PGD2 in the absence (A) and presence (B) of LPS (5 µg/ml), and the media were harvested 24 h later. Results initially derived as picograms per milligram wet tissue weight per 24 h and expressed as percentage of control (mean ± SEM, n = 2 placentas). *, P < 0.05 vs. controls.
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FIG. 6. Effects of PGD2 addition on 15d-PGJ2 production by human choriodecidual explants isolated from membranes from patients undergoing elective cesarean sections. Explants were treated with varying concentrations of PGD2 in the absence (open boxes) and presence (closed boxes) of LPS (5 µg/ml), and the media were harvested 24 h later. Results initially derived as picograms per milligram wet tissue weight per 24 h and expressed as percentage of control (mean ± SEM, n = 3 placentas). *, P < 0.05 vs. controls.
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Discussion
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We show for the first time that 9,11ß-PGF2 is present in human amniotic fluid. Additionally, our subsequent studies clearly demonstrate that human gestational tissues produce 9,11ß-PGF2 and that its production can be up-regulated by both proinflammatory cytokines and bacterial cell wall products. The lack of an increase in 9,11ß-PGF2 production by the placenta in response to cytokine treatment likely reflects the already high and probably saturated basal production rate of 9,11ß-PGF2. Interestingly, the tissue that had the lowest basal production (choriodecidua) appeared to be the most responsive when stimulated with proinflammatory cytokines. Given the position of the choriodecidua directly in contact with the myometrium and the equivalence of its contractile activity with that of PGF2, we believe that the myometrium is a major target for 9,11ß-PGF2 action. A study by Alfaidy et al. (26) demonstrated that PGF2 is involved in a feed-forward loop by which it increased enzymatic activity that in turn promoted further PG production that could potentially initiate labor. Hence, the effects of PGF2 on enzymatic activities in gestational tissues suggest that 9,11ß-PGF2 contributes to the mechanism(s) of parturition by more than a direct contractile effect.
Our results also support the view that enhanced flow from PGD2 via 9,11ß-PGF2 may play a part in the mechanisms of parturition (16). Also consistent with this hypothesis, 15d-PGJ2 has properties suggestive of a role in maintaining pregnancy (17). Furthermore, a role in the differentiation of trophoblasts has also been suggested (27). Moreover 15d-PGJ2 can have antiinflammatory actions that could reduce the progression of preterm labor (8).
The traditional view is that PGJ2 and its derivatives are formed nonenzymatically from PGD2; however, it has been reported that this conversion can be enhanced by estrogens (28). Because PGD2 is enzymatically converted to 9,11ß-PGF2, it is uncertain whether the cytokine and LPS effect on 9,11ß-PGF2 production by the gestational tissues is a reflection of an increase in enzymatic activity or simply more PGD2 being available for conversion. However, the results from experiments in which PGD2 was added to the incubations strongly indicated that the choriodecidua has the enzymes necessary to convert PGD2 to 9,11ß-PGF2 whereas the amnion has no such detectable activity. Those results also strongly indicated that the expression of the enzymes responsible for the conversion were not regulated by LPS because the actual amounts of 9,11ß-PGF2 produced were similar in the presence and absence of an LPS stimulation. Results from the cytokine treatment studies demonstrated that the amnion can produce 9,11ß-PGF2; hence, the enzymatic activities necessary for conversion may be induced by IL-1ß and TNF.
The increased concentrations of 9,11ß-PGF2 in the amniotic fluids taken at term after labor indicates that 9,11ß-PGF2 may contribute to the mechanisms that initiate parturition at term. The source of the 9,11ß-PGF2 in amniotic fluid is most likely the amnion; however, 9,11ß-PGF2 produced by the choriodecidua or placenta cannot be excluded without further investigation. Pooling of samples precluded statistical analysis on the differences in 9,11ß-PGF2 concentrations in the amniotic fluids. However, the doubling of the concentration of 9,11ß-PGF2 in the TIL group, compared with the TNL group, is consistent with a previously reported increase in PGE2 and PGF2 during labor (29), although in that study, an approximate 10-fold and 3-fold increase in PGE2 and PGF2, respectively, was observed. The relative concentrations of PGE2 and PGF2 described were, however, significantly higher than the concentrations of 9,11ß-PGF2 reported here, which may indicate more of a supporting role in the mechanisms of labor for 9,11ß-PGF2.
Little is known of the regulation of 9,11ß-PGF2 production other than increased urinary concentrations with bronchoconstriction, which can be used as a marker of mast cell activation (30). Our results demonstrate that 9,11ß-PGF2 is produced by human gestational tissues and that its production can be regulated by inflammatory mediators. Other PGJ2-derived PGs, such as 15d-PGJ2, have been shown to have major effects on gestational tissues (17, 31). These latter effects taken together with the regulatory role in enzymatic activity (26) demonstrated for PGF2 suggests that there are multiple potential role(s) for 9,11ß-PGF2 in human pregnancy and parturition. In conclusion, 9,11ß-PGF2 may play a hitherto unanticipated role(s) in pregnancy and labor at term and preterm. Further studies will be needed to establish the exact roles and regulation of 9,11ß-PGF2 in both the setting of infection-associated preterm labor and term delivery.
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Acknowledgments
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We are grateful to the theater staff at National Women’s Hospital for the collection of placentas, with a very special thanks to Oliva Tupusi for the organization of patient consent. We also thank and acknowledge Elizabeth Robinson (Department of Community Health, University of Auckland, Auckland, New Zealand) for her advice on the statistical analysis of the data.
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Footnotes
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This work was supported by grants from the Health Research Council of New Zealand and the Auckland Medical Research Foundation.
First Published Online April 19, 2005
Abbreviations: 15d-PGJ2, 15-Deoxy12, 14-prostaglandin J2; LPS, lipopolysaccharide; PG, prostaglandin; PPAR, peroxisome proliferator-activated receptor; PTIL, preterm labor; PTNL, preterm no labor; TIL, term labor; TNL, term no labor.
Received December 20, 2004.
Accepted April 7, 2005.
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Abstract
Introduction
