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Original Studies |
on the Activity and Expression of Prostaglandin H Synthase-2 and the NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase in Cultured Term Human Villous Trophoblast and Chorion Trophoblast Cells1
Medical Research Council Group in Fetal and Neonatal Health and Development, Department of Physiology, and Obstetrics and Gynecology, University of Toronto (F.P., J.R.G.C.), Toronto, Ontario, Canada M4Y 1M8; and the Department of Obstetrics and Gynecology, Universita Cattolica del Sacro Cuore (F.P., A.C.), Rome 00168, Italy
Address all correspondence and requests for reprints to: Dr. F. Pomini, Universita Cattolica del Sacro Cuore, Department of Obstetrics and Gynecology, L.go A. Gemelli No. 8, Rome 00168, Italy. E-mail: fpomini{at}mix.it
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF) and
interleukin-1ß (IL-1ß), two inflammatory cytokines in amniotic
fluid, have been shown to rise during chorioamnionitis. This is
probably related to activation of the immune system in order to
intensify the inflammatory process and to protect the maternal and
fetal organism from infectious agents. These cytokines activate the PG
biosynthetic pathway in several tissues, but few studies have examined
effects on PG-metabolizing enzymes. When PGs are produced by increased
synthesis and/or decreased metabolism at the chorio-decidual interface,
labor can be induced. Interleukin-10 (IL-10) is known to act as an
antiinflammatory cytokine. The goals of this study were to evaluate the
interaction of IL-10 with IL-1ß and TNF on PG synthesis and to
determine the effects of IL-10, IL-1ß, and TNF on PG metabolism
using purified cultures of villous trophoblast and chorion trophoblast
cells prepared from placentas of patients at term. Cells were treated
with IL-1ß and TNF with or without IL-10 for various times up to
24 h. Levels of messenger ribonucleic acid (mRNA) encoding PGH
synthase-2 (PGHS-2) and NAD+-dependent
15-hydroxyprostaglandin dehydrogenase (PGDH) were quantified by
Northern blotting, and PGE2 and
13,14-dihydro-15-keto-PGF2 (PGFM) output in the medium
was measured by RIA. IL-1ß increased PGHS-2 mRNA and PGE2
output from villous and chorion trophoblasts and decreased PGDH mRNA in
villous trophoblasts (all P < 0.05). These effects
were reversed by IL-10. We found no change in PGHS-2 mRNA or
PGE2 output in either trophoblast type treated with TNF,
but TNF reduced PGDH mRNA in villous trophoblast, and this effect
was reversed by IL-10 (both P < 0.05). We conclude
that proinflammatory cytokines can influence PG output through effects
on PG synthesis and metabolism and that these effects may be opposed by
an antiinflammatory cytokine. These interactions may be important in
the progression of preterm labor with underlying infection and in term
labor in regions of the uterus where cytokine production is increased. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF) and
interleukin-1ß (IL-1ß) are two cytokines associated with
inflammatory processes (1, 2). They are produced at basal levels by
several fetal and maternal tissues (3, 4), and their concentrations in
amniotic fluid are increased in clinical or subclinical
chorioamnionitis (5, 6). These cytokines influence not only the immune
response, but can also activate the PG biosynthetic pathway in several
feto-maternal tissues (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). Few studies, however, have examined
their effects on key PG-metabolizing enzymes (22). When PGs are
produced at the feto-maternal (chorio-decidual) interface, labor can be
induced.
IL-10 has been commonly characterized as an antiinflammatory cytokine,
acting on neutrophils and reducing the effect of proinflammatory
cytokines such as IL-12 and IL-6 (23, 24). The effects of IL-10 on
TNF are less clear, because IL-10 has been shown to raise the
production of the TNF surface and soluble receptors, the former
amplifying TNF action, the latter reducing its effects (25).
Recently, IL-10 has been shown to reduce PG production by
down-regulating the inducible PGHS-2 isoform in stimulated neutrophils
(26). Because IL-10 is normally produced by some fetal and maternal
tissues (27, 28), it was hypothesized that it could play an important
role in modulating cytokine-induced PG output during
infection-associated preterm labor and in regions of the uterus, such
as the lower segment, in labor at term.
The action of PG on the myometrium and cervix could result in part from
the relative activities of PG-synthesizing and -metabolizing enzymes
(29). Characteristics of key PG metabolic enzymes have been described
in detail (30), and the NAD+-dependent
15-hydroxyprostaglandin dehydrogenase (PGDH) enzyme occupies a crucial
role (30). This enzyme is expressed in placental syncytiotrophoblast
and in chorionic trophoblast cells. The activity of PGDH in the chorion
is reduced in 10–15% of idiopathic preterm labor (31) and in many
cases of infection-associated preterm labor (32). Furthermore, PGDH
expression and activity are lower in chorion obtained at term from the
region of the internal cervical os (33), a potential region of
increased production of cytokine. We therefore determined the effects
of proinflammatory cytokines, IL-1ß and TNF, on PG synthesis and
metabolism in trophoblast cells prepared from chorion and placenta from
patients at term and evaluated whether the antiinflammatory IL-10 can
reverse the effects of IL-1ß and TNF on the PG biosynthetic and
metabolic pathway.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Four placentas were collected from term (>37 weeks gestational age) normal pregnancies. Exclusion criteria were multiple pregnancy, induction of labor with PG, treatment with any PGHS inhibitor during the 3-week period before admission to the hospital, and/or patient had not been routinely followed in the Perinatology Division of Mount Sinai Hospital (Toronto, Canada). None of the patients was positive for group B streptococcus at the prenatal screening. Informed consent was obtained from all patients.
Membranes and placentas were harvested under strictly sterile conditions during all of the procedures. Immediately after placental expulsion, the chorion was bluntly separated from the amnion, cut around the placental margins, and immersed in sterile cold saline. Pieces of placental villi were also cut from the maternal side and immersed in cold sterile saline. The placenta and chorion were then taken to the laboratory for further processing. The mean time between expulsion of the placenta and the start of processing of the tissue was 35 ± 9 (±SEM) min.
Cell culture
Villous trophoblast and chorion trophoblast cells were isolated and cultured using a modification of the technique described by Kliman et al. (34) as published previously (32, 35). Approximately 60 g cotyledon tissue were digested with 0.125% trypsin (Life Technologies, Inc., Grand Island, NY) and 0.02% deoxyribonuclease I (Sigma, St. Louis, MO) in DMEM (Life Technologies, Inc.) containing 0.05% gentamicin sulfate (Life Technologies, Inc.), three times for 30 min each time. The chorion, after the removal of decidua and blood clot, was digested three times for 60 min each time with the same digestion medium supplemented with 0.2% collagenase (Sigma). The dispersed villous or chorio-decidua cells were filtered through a 200-µm pore size nylon gauze and loaded onto a 42-mL preformed discontinuous Percoll (Sigma) gradient of 5–70% in 5% steps of 3 mL each, then centrifuged at room temperature (1200 x g) for 20 min. Cells between the density marker beads (Sigma) of 1.049 and 1.062 g/mL were collected and counted with a hemocytometer in the presence of 50% trypan blue to assess viability (35). The cells were then plated in 24-well plates (Corning, Costar, Cambridge, MA) at a density of 1,000,000 cells/mL·well, in 100-mm petri dishes (Corning) at a density of 15,000,000 cells/15 mL·dish, or in 8-chamber slides at a density of 500,000 cells/0.5 mL·well in DMEM culture medium containing 10% FCS (Life Technologies, Inc.) and 0.05% gentamicin sulfate. Cells were then cultured for 5 days at 37 C in 5% CO2 and 95% air before treatment. All of the preparations of chorion and villous cells were examined daily with an inverted microscope to ensure that they were free of contamination or infection.
Treatment
After 5 days, most of the villous trophoblast cells had
aggregated to form a syncytium. Chorion and placenta cells were then
washed with FCS-free medium equilibrated at 37 C containing 1) medium
alone, 2) IL-1ß (recombinant human IL-1ß, 1 ng/mL; R & D Systems,
Minneapolis, MN), 3) TNF (recombinant human TNF; 10 ng/mL; R & D
Systems), 4) IL-10 (recombinant human IL-10; 5 ng/mL; R & D Systems),
5) IL-1ß (1 ng/mL) and IL-10 (5 ng/mL), and 6) TNF (10 ng/mL) and
IL-10 (5 ng/mL). At successive time points (2, 4, 8, and 24 h) the
medium was collected, frozen, and stored at -80 C for further
analysis. Separate wells were used for each time point. Cells in the
petri dishes were treated for 4 h only, as not enough cells could
be collected for every treatment for each time point. After the medium
had been collected, some of the chorion and villous cells were treated
at 37 C with fresh medium containing 50% trypan blue and then
immediately checked for cell viability. For both chorion and villous
cultures, mean viability was always more than 90%. Representative
cultures on the day of treatment were stained with cytokeratin
(DAKO Corp., Santa Barbara, CA) at a dilution of 1:1000,
or with vimentin (DAKO Corp.) at a dilution of 1:100 to
determine the proportion of immunopositive cells (35, 36). Cells were
counterstained with Carazzi’s hematoxylin. Both placental and chorion
cultures were predominantly cytokeratin positive (>90% and >
80%, respectively) and vimentin negative. Similar results were
obtained for the different cell preparations.
RIA
The activity of PGDH was assessed by measuring the
13,14-dihydro-15-keto metabolite of PGF2
(PGFM) content in duplicate aliquots of the collected medium, as
previously described (35), using a specific PGFM antiserum (1:1500
dilution; Oxford Biomedical, Oxford, MI). Unknown sample values were
determined using the Four Parameter Computer Program (P. Munson, D.
Rodbard, and M. L. Jaffe, version 4.0). The concentration of
PGE2 in the medium was assayed with a similar
procedure, using a PGE2 antiserum (1:4000
dilution; Oxford Biomedical) and
[3H]PGE2 (Amersham International, Aylesbury, UK). Previous studies showed that
PGE2 was the principle primary PG produced by
these cells in culture. The mean intra- and interassay coefficients of
variation were 6.6% and 9.2% for PGE2, and
4.5% and 12.4% for the PGFM RIAs. Assay sensitivity was routinely
approximately 15 pg/tube for PGE2 and 20 pg/tube
for PGFM.
Ribonucleic acid (RNA) extraction and Northern blotting
The cells in the petri dishes were mechanically dispersed by
scraping for 1 min in the presence of Trizol reagent (2 mL; Life Technologies, Inc.) and then incubating for 5 min. In
preliminary experiments (unpublished data) we determined that 2 mL
Trizol reagent were sufficient to obtain a suitable yield
(OD260/280nm, >1.6) of the total RNA extracted
from the chorion and villous cells plated in the petri dishes. The rest
of the procedures followed the manufacturer’s instructions, except
that the incubation with isopropyl alcohol was performed at 4 C for 20
min. The RNA concentration and the purity of each sample were
determined by measuring the absorbance at 260 nm and evaluating the
260:280 nm ratio (Ultrospec 2000, Pharmacia Biotech, Baie
d’Urfe, Canada); samples were then stored at -80 C in 75% ethanol.
Northern blotting was subsequently performed as follows. Thirty
micrograms of extracted total cellular RNA plus one RNA ladder
(Life Technologies, Inc.) were size fractionated by
horizontal electrophoresis (Horizon 20x25, Life Technologies, Inc.) in a 1.2% agarose/formaldehyde gel and transferred to a
nylon membrane (Z-Probe Blotting Membrane, Bio-Rad Laboratories, Inc., Mississauga, Canada). The blots were then hybridized using
an 800-bp fragment of the PGDH complementary DNA (cDNA) sequence as
probe (32). The fragment was labeled with
-[32P]deoxy-CTP (Amersham International) using the random priming method (Ready to Go,
Pharmacia-Biotech) and was separated from unincorporated
oligonucleotides by passing it through a nick column (Pharmacia Biotech). After autoradiographic exposure, the blots were
stripped and reprobed with a cDNA to human PGHS-2 (Oxford Biomedical)
labeled as outlined above. After autoradiographic exposure, the blots
were stripped again and reprobed with a cDNA to mouse 18S ribosomal RNA
(rRNA) to allow for correction of variations in gel loading and
transfer. The relative optical densities (ROD) were determined using
computerized image analysis (MCID, Imaging Research, Inc.,
St. Catherines, Canada). The values for ROD were determined after
different exposure times to ensure that values were obtained within the
linear range of the autoradiographic film. Results are expressed as the
ratio of the RODs of the PGDH or PGHS-2 messenger RNA (mRNA):18S rRNA
hybridization signals.
Data analysis
The shape of the distribution of the variables was tested with the Kolmogorov-Smirnov-Lilliefors test. ANOVA and the ANOVA for repeated measures were used to compare the results before and after treatments and the effects of IL-10; when only two variables were analyzed, two-tailed paired and unpaired Student’s t test were used. Only if both paired and unpaired tests resulted in P < 0.05 was the difference considered significant. Rank transformation was used when necessary. Power analysis was performed after each comparison and reported when 1-ß < 0.8. SigmaStat 1.0 for Windows (Jandel Scientific Software, San Rafael, CA) and Cricket Graph 1.3.1 for Macintosh (Cricket Software) were used for the analysis and graphing of the data. Data are expressed as the mean ± SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PGHS-2 mRNA was present as a major 4.4-kb transcript by Northern
blot. After incubation with IL-1ß for 4 h, the PGHS-2/18S ratio
increased significantly by 71% (P < 0.01; Fig. 1
). Treatment with IL-10 increased the
PGHS-2/18S ratio by 36% (P < 0.02; Fig. 1), whereas
treatment with IL-10 and IL-1ß together resulted in a reduction in
the PGHS-2/18S ratio (P < 0.02) from values seen after
IL-1ß treatment.
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). IL-10 alone had
no significant effect on PGE2 output, but
combined IL-1ß and IL-10 treatment produced lower
PGE2 output at 8 and 24 h (P
< 0.05) compared to the effects of IL-1ß alone.
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The PGDH cDNA hybridized with two species of mRNA of 2.0 and 3.4
kb as reported previously (31). Addition of IL-1ß led to a modest
(18%) reduction in levels of PGDH mRNA (P < 0.05;
Fig. 3). IL-10 alone had no effect on
PGDH mRNA, but prevented the decline in PGDH mRNA seen after the
addition of IL-1ß (Fig. 3).
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Effects of TNF on villous trophoblast PGHD-2 and PGDH expression
and on PGE2 and PGFM output
We did not find significant effects of TNF on levels of PGHS-2
mRNA or on output of PGE2 (data not shown), nor
were there any significant interactions of TNF with IL-10 on these
measurements. TNF produced a modest (10%), but statistically
significant (P < 0.05; Fig. 4), decrease in levels of PGDH mRNA
compared to those in control cultures and those in cultures treated
with TNF and IL-10, which were not different (P >
0.05) from the control values (Fig. 4). PGFM output tended to be lower
in cultures treated with TNF at each time point, but the mean values
were not statistically different from the control (P >
0.05).
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on chorion trophoblast PGHS-2
and PGDH expression and on PGE2 and PGFM
output
IL-1ß stimulated a significant increase (285%) in PGHS-2 mRNA
levels in chorion trophoblast cells (P < 0.02; Fig. 5), but this effect was not altered
significantly in the presence of IL-10. There were no significant
effects of 4-h treatments with TNF or IL-10 alone or with TNF
plus IL-10 on PGHS-2 mRNA in chorion trophoblasts.
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) that was unaffected by
the presence of IL-10. We found no significant effect of any of the
cytokines on levels of PGDH mRNA in chorion cells or in PGFM output
from chorion cell cultures for up to 24 h (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our preparations of villous and chorion trophoblasts were characterized by cytokeratin and vimentin staining as discussed previously (35), and the cells are predominantly cytokeratin positive. However, in chorion and placenta, PGHS-2 has been localized by immunostaining to fibroblasts and macrophages in addition to trophoblasts (37, 38). Therefore, we cannot conclusively determine that trophoblasts are the only responsive cell type. Resolution of this issue will require extremely pure cell preparations and localization of IL-1ß receptor to these cells (9). We found that IL-1ß not only increased PGHS-2 expression, but also decreased, modestly, levels of PGDH mRNA. Previous studies have localized PGDH predominantly to trophoblast in chorion and to syncytiotrophoblast and intermediate trophoblasts of the placental villi (31, 32). Double labeling studies will be required to determine the extent to which PGHS-2 and PGDH are localized to the same cells or to adjacent cells in vivo and, hence, whether cytokines such as IL-1ß might simultaneously affect both PG synthesis and metabolic pathways in the same or adjacent cells. Current evidence indicates that PGHS-2 may be localized to the nuclear envelope and to the endoplasmic reticulum of responsive cells (39, 40), whereas PGDH is predominantly cytosolic (30). Thus, even within the same cell there is likely to be compartmentalization of the downstream effects of cytokine.
Keelan et al. (22) reported recently that PGDH mRNA levels
were reduced to 25% of the control level in trophoblast cells treated
with IL-1ß, a greater degree of inhibition, but a similar pattern as
in the present study. Despite this finding, our results show that the
output of both PGE2 and PGFM from villous
trophoblasts rose during exposure to IL-1ß. We suggest that
stimulation of PG synthesis provides more substrate for PGDH so that
PGFM output continues to rise even though PGDH mRNA levels have
decreased. In addition, changes in steady state levels of PGDH mRNA may
not parallel changes in PGDH protein or enzyme activity, such that PGDH
protein levels may still be elevated despite lowered levels of its
mRNA. As the Km of PGDH for
PGE2 and PGF2 range from
30–130 µmol/L (30), much greater than the concentration of PG in the
medium, up-regulation of PGHS-2 is likely to be more important than
down-regulation of PGDH. In unpublished studies we found that the
effects of IL-1ß on PGHS-2 and PGDH were dose dependent. Further
studies are needed to elucidate differences in synthesis and metabolism
of PG at different concentrations of exogenous IL-1ß and to relate
these to the endogenous production of cytokines by the cell populations
in culture.
We found no effect of IL-1ß on PGDH mRNA levels or PGFM output by
purified chorion trophoblast cells, in contrast to the effects on
villous trophoblasts. Brown et al. (41) also reported the
lack of an IL-1ß effect on PGDH activity in disks of full thickness
membranes maintained in culture. In contrast to the report of Keelan
et al. (22), in which inhibition of PGDH mRNA was similar
after IL-1ß and TNF treatment, we found only minimal, although
significant, reduction of PGDH mRNA in villous trophoblasts treated
with TNF and no effect of TNF on levels of mRNA encoding PGDH or
PGHS-2 in chorion trophoblasts. This result was also surprising given
that several previous reports have shown increased PG output from
amnion WISH cells, first trimester human trophoblasts, and term chorion
trophoblasts treated with TNF (16, 17, 18, 19, 20, 21). We presume that differences
in culture technique and/or conditions, particularly the time at which
tissue was collected, in earlier studies in relation to labor or the
availability of soluble TNF receptor to mediate its activity may
account for this variation.
Addition of IL-10 to villous trophoblast cultures treated with IL-1ß attenuated the up-regulation of PGHS-2 and the output of PGE2 and reversed the reduction in PGDH mRNA levels seen in response to the proinflammatory cytokine. Opposing effects of proinflammatory and antiinflammatory cytokines on PGHS expression and PG output have been reported previously. Our finding that the effects of IL-1ß on PG synthesis and metabolism can be attenuated or reversed by IL-10 suggests that the interaction between different cytokines and eicosanoids in vivo will be very difficult to evaluate from in vitro studies in which precise combinations of two or three different compounds are added to cells in culture. A nuclear factor-IL-6 regulatory element has been identified in the upstream promoter region of the PGDH gene (42), but the mechanisms by which various cytokines differentially affect promoter activity of NAD+-dependent PGDH or affect the stability of mRNA are presently unknown.
Previously we reported that expression of PGDH mRNA and/or protein as well as activity were lower in chorion from patients at idiopathic preterm labor and in preterm labor with infection (31, 32) and were reduced in lower segment chorion at the time of labor (33). It is clear that regulation of this enzyme is multifactorial (35, 42). We have reported that basal PGDH expression and activity of trophoblast cells in vitro are sustained by progestogens, whereas glucocorticoids such as cortisol and dexamethasone decrease PGDH expression (35). The present study indicates that the enzyme can also be down-regulated by proinflammatory cytokines, although the effects were seen only in villous trophoblast cells. The possibility that cytokines of different classes may have opposing actions on key enzymes of PG synthesis and metabolism adds a further dimension to an already complex series of relationships, an understanding of which is critical to recognition and treatment of the patient in preterm labor.
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Footnotes |
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2 Postdoctoral Fellow in the Department of Physiology of the
University of Toronto, Toronto, Canada, supported by the National
Research Council of Italy and by Takeda Co.
Received February 23, 1999.
Revised August 10, 1999.
Accepted August 18, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in human
amniotic WISH cells by various stimuli occurs through distinct
intracellular mechanisms. J Pharmacol Exp Ther. 280:1065–1074. and its soluble receptors on arachidonic acid
metabolism in ED27 first trimester trophoblast. J Soc Gynecol Invest. 4:94A.
stimulates increased expression of prostaglandin
endoperoxide H synthase type 2 mRNA in amnion-derived WISH cells. J Mol
Endocrinol. 20:221–231.[Abstract]
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