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Receptor Expression by Interleukin-1ß in Cultured Human Granulosa-Luteal Cells1
Departments of Obstetrics and Gynecology and Clinical Chemistry (K.N., A.R.) and the Haartman Institute, Department of Bacteriology and Immunology (O.R., A.R), University of Helsinki, Helsinki, Finland
Address all correspondence and requests for reprints to: Dr. Ari Ristimäki, Research Laboratory, Department of Obstetrics and Gynecology, University of Helsinki, Haartmaninkatu 2, SF-00290 Helsinki, Finland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(FP) in
human granulosa cells obtained from women undergoing oocyte retrieval
for in vitro fertilization. Freshly isolated granulosa
cells express Cox-2 and FP receptor messenger RNAs (mRNAs). FP receptor
mRNA is also expressed in cultured human granulosa-luteal (GL) cells,
but Cox-2 transcripts are expressed only upon induction.
Interleukin-1ß (IL-1ß) elevated Cox-2 mRNA steady state levels in a
concentration-dependent manner, and kinetic studies showed that Cox-2
mRNA levels were already induced at the 2 h point and returned to
the basal level after incubation for 24 h. The protein synthesis
inhibitor, cycloheximide, induced Cox-2 mRNA expression and potentiated
the effect of IL-1ß. Degradation of Cox-2 mRNA was inhibited by
IL-1ß, which suggests regulation at the posttranscriptional level.
IL-1ß also induced the expression of Cox-2 protein, as detected by
immunofluorescence staining using Cox-2-specific polyclonal antibodies.
Further, IL-1ß-induced synthesis of prostanoids was blocked by a
Cox-2-specific inhibitor, NS-398. In addition, hCG induced Cox-2 mRNA
expression and potentiated the effect of IL-1ß. However, in contrast
to the rapid and transient effect of IL-1ß on Cox-2 mRNA, the effect
of hCG followed slower kinetics. We have previously shown that hCG
induces expression of human FP receptor mRNA in cultured human GL
cells. We now show that IL-1ß induces FP receptor mRNA in a time- and
concentration-dependent manner. Our data suggest that Cox-2 and FP
receptor are coexpressed in freshly isolated human granulosa cells and
that their expression is up-regulated by IL-1ß and hCG in cultured
human GL cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Most prostanoids exert their actions through specific cell surface
receptors, and the response to prostanoids could potentially be
modulated by regulation of expression of the respective receptor.
PGF2 is a prostanoid that triggers regression of corpus
luteum (15). It acts via the PGF2 receptor (FP), which
is a putative seven-transmembrane domain receptor that signals through
G proteins that activate phospholipase C, which leads to formation of
inositol trisphosphate and a subsequent increase in cytosolic free
calcium (16, 17). Human FP receptor has been cloned from uterine (16)
and placental tissues (17). We have recently shown that the expression
of FP receptor is induced by hCG and down-regulated by phorbol
12-myristate 13-acetate (PMA) in human granulosa-luteal (GL) cells
(18). Further, the expression of FP receptor is induced by LH and
decreased by PMA and PGF2 in ovine corpus luteum (19)
and is induced by hCG and forskolin in cultured bovine granulosa cells
(6).
Interleukin-1 (IL-1) is an important mediator of inflammation (20). Several lines of evidence suggest that IL-1 may also have a regulatory role in the ovary: 1) IL-1ß is synthesized in ovarian stroma by macrophages (21); 2) IL-1-like activity is present in human (22) and porcine (23) follicular fluid; and 3) synthesis and expression of IL-1ß, its receptor, and receptor antagonist have been localized in human ovarian granulosa cells (24). Finally, IL-1ß induces ovulation in perfused rat (25, 26) and rabbit (27) ovaries. The proovulatory effect of IL-1ß may be facilitated by prostanoids, as IL-1ß has been shown to stimulate PG production in rat whole ovarian dispersates (28) and preovulatory follicles (22) and in cultured human granulosa cells (29, 30).
The objective of the present study was to examine the expression of Cox enzymes in freshly isolated human granulosa cells and to investigate whether Cox-2 and FP receptor expression can be regulated by IL-1ß in cultured human GL cells.
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Materials and Methods |
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RNA isolation and Northern and dot blot hybridization analyses
Cytoplasmic RNA was isolated from cultured granulosa cells using
the Nonidet P-40 lysis procedure (31) or TriZol reagent (Life
Technologies). Total RNA from freshly isolated granulosa cells was
extracted using the guanidine isothiocyanate-cesium chloride method
(32). For Northern blot analysis, 10–20 µg RNA were first denatured
in 1 M glyoxal, 50% dimethylsulfoxide, and 10
mM phosphate buffer at 50 C for 60 min and then
electrophoresed through 1.2% agarose gel. The RNA was transferred to
Hybond-N nylon membranes (Amersham International, Aylesbury, UK). For
dot blots, 1–2 µg RNA were denatured in 7.5% formaldehyde and
6 x SSC (1 x SSC = 0.15 M NaCl and 0.015
M sodium citrate, pH 7.0) at 60 C for 30 min and then
spotted onto nylon membranes using a 96-well Minifold device
(Schleicher and Schuell, Dassel, Germany). All blots were baked for
1 h at 80 C and cross-linked under UV light for 6 min (Reprostar
II UV, Camag, Muttenz, Switzerland). Human Cox-1, Cox-2, and
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) complementary DNAs
(cDNAs) (33) were labeled using [-32P]deoxy-CTP
(DuPont-New England Nuclear, Boston, MA) and the Prime-a-Gene kit
(Promega, Madison, WI). Linear amplification labeling was performed as
previously described (18, 34) to obtain a single stranded human FP
receptor cDNA probe. Probes were purified with nick columns (Pharmacia)
and used at 1 x 106 cpm/ml. Hybridizations were
performed at 42 C for 16 h in solution containing 50% formamide,
6 x SSC, 0.1% Ficoll, 0.1% polyvinylpyrrolidone, 0.1% BSA, 100
µg/ml herring sperm DNA, 100 µg/ml yeast RNA, and 0.5% SDS.
Membranes were washed three times at 50 C for 15 min each time in
0.1 x SSC and 0.1% SDS. Dot blots were quantitated using a
Fujifilm IP-Reader Bio-Imaging Analyzer BAS 1500 (Fuji Photo Co.,
Tokyo, Japan) and MacBas software supplied by the manufacturer.
Northern blots were visualized by autoradiography.
Reverse transcriptase-PCR (RT-PCR)
Total RNA (1 µg) was converted to cDNA and PCR amplified with
Cox-1, Cox-2, and GAPDH sense and antisense primers as described
previously (33). Cox-1 and Cox-2 were amplified for 35 cycles, and
GAPDH was amplified for 30 cycles of denaturation at 94 C for 1 min,
annealing at 60 C for 1 min, and extension at 72 C for 1 min. Amplified
products were electrophoresed through 1% agarose gel and visualized by
ethidium bromide staining.
Assay of 6-keto-PGF1 and measurement of
DNA content of cell cultures
GL cells were incubated with arachidonic acid (10
µM; Sigma) for 15 min. Conversion of arachidonic acid to
prostacyclin (PGI2) was evaluated by measuring the
production of its stable hydrolysis product,
6-keto-PGF1, from cell culture medium by RIA,
employing a specific antibody (35) and a tritiated
6-keto-PFG1 (Amersham). DNA concentrations in cell
cultures were measured using a slightly modified method originally
described by Rymaszewski et al. (36). Briefly, the cells
were lysed in alkaline EDTA and neutralized with
KH2PO4, followed by the addition of
fluorochrome bisbenzimidazole (Hoechst 33258, Pharmacia) and
measurement of fluorescence by DyNA Quant 200, as suggested by the
manufacturer (Hoefer Pharmacia Biotech, San Francisco, CA).
Immunofluorescence staining
For immunofluorescence, GL cells were grown on chamber slides
(Nunc, Naperville, IL) for 6 days and then treated with or without
IL-1ß (10 ng/ml) for 4 h. The cells were fixed with ice-cold
acetone for 10 min, and the chambers were washed three times for 10 min
each time in PBS (HyClone, Northumberland, UK). Nonspecific binding of
antibody was blocked with 1% BSA in PBS for 15 min. The samples were
incubated with human Cox-2 polyclonal antibodies (Cayman Chemical Co.)
at room temperature for 30 min and then washed with PBS three times for
10 min each time. The secondary antibody, fluorescein
isothiocyanate-conjugated goat antirabbit IgG (Jackson ImmunoResearch
Laboratories, West Grove, PA), was added and incubated for 30 min, and
the samples were then washed with PBS three times for 10 min each time.
As a negative control, the cells received the same treatment with the
exception of the primary antibody.
Statistical analysis
Statistical significance for a single comparison was calculated
using Student’s t test. For multiple comparison, the
t test was used only if one-way ANOVA indicated a
significant difference. All results are shown as the mean ±
SEM, and P < 0.05 was selected as the
statistically significant value. All experiments were repeated at least
three times, and each experiment consisted of three separate
observations.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) or RT-PCR (Fig. 1B). In Northern blot
analysis, 4.6- and 2.8-kb transcripts were detected. The transcript
sizes are consistent with our earlier results obtained in human lung
fibroblasts, and they are likely to represent alternatively
polyadenylated Cox-2 isoforms (37). Cox-1 mRNA was detected in
uncultured and cultured cells by RT-PCR (Fig. 1B), but not by Northern
blot analysis. FP receptor mRNA was detected by Northern blot
hybridization in both freshly isolated cells and cultured GL cells
(Fig. 1A).
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). As shown in Fig. 2B, the effect of IL-1ß was concentration dependent. To examine whether
the cell culture stage has an effect on the induction of Cox-2 mRNA, GL
cells were treated with IL-1ß (10 ng/ml) or hCG (30 ng/ml) for 8
h at days 2, 5, and 7 after initiation of the cultures. As shown in
Fig. 3A, IL-1ß induced Cox-2 mRNA at
all stages of culture. This was in contrast to the results obtained
with hCG, which did not initially (on day 2) have an effect on Cox-2
mRNA expression. Interestingly, hCG potentiated the effect of IL-1ß
on Cox-2 expression (Fig. 3B). Incubation of GL cells for 2 h with
cycloheximide, an inhibitor of protein synthesis, resulted in an
approximately 4-fold induction of Cox-2 mRNA steady state levels.
Cycloheximide also potentiated the effects of IL-1ß, hCG, and
8-bromo-cAMP (Fig. 4). IL-1ß did not
modulate Cox-1 mRNA expression, as detected by RT-PCR (not shown).
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), and IL-1ß was able to inhibit
degradation of the Cox-2 transcript (Fig. 5B).
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). We
also examined the effect of a Cox-2-specific inhibitor, NS-398, on
IL-1ß-induced prostanoid production in GL cells by measuring the
concentrations of 6-keto-PGF1, a stable metabolite of
prostacyclin. IL-1ß increased 6-keto-PGF1
concentrations in the cell culture medium approximately 2-fold (Fig. 7A), and this induction was blocked by
NS-398 (Fig. 7B).
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). 8-Bromo-cAMP induced Cox-2
expression with similar kinetics as hCG (data not shown).
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)
and was concentration dependent (Fig. 9B). IL-1ß together with hCG
resulted in 2-fold induction compared with that produced by IL-1ß or
hCG alone (Fig. 9B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Wong et al. (39) and Sirois et al. (40)
previously reported that IL-1ß does not induce the expression of
endogenous Cox-2 or activity of a transfected Cox-2 promoter construct
in rat granulosa cells. However, induction of Cox-2 mRNA has been
detected by RT-PCR in rat preovulatory granulosa cells (41). Further,
IL-1ß has been shown to stimulate synthesis of prostanoids in rat
whole ovarian dispersates (28) and preovulatory follicles (21), and the
synthesis of PGE2 and PGF2 has been shown to
be stimulated by IL-1ß in cultured human granulosa cells (29, 30). In
our experiments IL-1ß treatment resulted in a rapid and transient
induction of Cox-2 mRNA in cultured human GL cells. Expression of Cox-2
protein was also stimulated by IL-1ß in these cells. In addition,
IL-1ß-induced conversion of arachidonic acid to a prostanoid, which
was inhibited by the Cox-2-specific inhibitor, NS-398. This suggests
that elevated expression of Cox-2 enzyme is important in
IL-1ß-induced prostanoid production in human ovarian granulosa
cells.
Inhibition of protein synthesis induces expression of Cox-2 mRNA
in several cell types (33, 42). However, cycloheximide did not induce
Cox-2 mRNA expression in rat granulosa cells (43), and it decreased the
induction of Cox-2 mRNA stimulated by gonadotropins (44). In the
present study cycloheximide induced the expression of Cox-2 mRNA and
potentiated the effects of IL-1ß, hCG, and 8-bromo-cAMP, indicating
that induction of Cox-2 mRNA expression is not dependent on protein
synthesis in human GL cells. The mechanism by which cycloheximide
induces Cox-2 mRNA is not known, but it is possible that it inhibits
the synthesis of proteins responsible for the rapid degradation of
Cox-2 transcripts. IL-1 and IL-1ß have been previously shown to
induce Cox-2 mRNA in fibroblasts and endothelial cells by inducing
transcription and preventing degradation of the Cox-2 mRNA (33, 37).
IL-1ß also stabilizes Cox-2 message in mesangial cells (45).
Induction of Cox-2 mRNA by IL-1ß in human GL cells seems to depend at
least partially on posttranscriptional stabilization of Cox-2
transcript.
Cox-2 mRNA and protein have been shown to be rapidly and transiently induced by ovulatory concentrations of gonadotropins via cAMP-dependent protein kinase A (PKA) pathway (3, 43, 46). In rat granulosa cells Cox-2 mRNA levels peak after 4 h and disappear after incubation for 6 h. Induction of Cox-2 by hCG in bovine granulosa cells from preovulatory follicles follows slower kinetics and is sustained (5, 6), which was also the case in our experiments with human GL cells. We detected similar kinetics in induction of Cox-2 mRNA with 8-bromo-cAMP as with hCG, suggesting that Cox-2 is also induced via PKA pathway in human GL cells. Cox-2 is also induced by other signaling pathways, including protein kinase C (PKC) and tyrosine kinases, in rat granulosa cells (47). Involvement of the PKC pathway in the induction of Cox-2 in human granulosa cells is supported by the findings that PMA increases prostacyclin production (48) and that PMA up-regulates Cox-2 mRNA levels in human GL cells (our unpublished observation). In our study, Cox-2 expression was stimulated by hCG only when the GL cells were cultured for more than 2 days. A similar lag period in responsiveness of other parameters to hCG has been observed in previous studies using this cell culture model (18, 34). This may reflect the down-regulation of LH/hCG receptors or their signaling pathways in response to hormone treatment received by the granulosa cell donors. Interestingly, simultaneous administration of hCG and IL-1ß resulted in synergistic induction of Cox-2 mRNA in GL cells.
Our group has previously shown that the FP receptor is induced after incubation for 24–48 h with hCG in human GL cells (18). We now show that IL-1ß induces FP receptor mRNA expression in GL cells. Interestingly, the induction followed slower kinetics than that of Cox-2, suggesting that the mechanism of induction may be different. However, as FP receptor Cox-2 mRNAs were induced with similar kinetics by hCG, these transcripts may be coregulated via the PKA pathway in human GL cells.
Our data show that IL-1ß-induced production of prostanoids is dependent on Cox-2 expression in cultured human GL cells. We also show that FP receptor mRNA is regulated by IL-1ß in human GL cells. To better define the biological significance of the present findings, additional studies are in progress to further characterize the role of prostanoid-forming enzymes and PG receptors in the human ovary.
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Acknowledgments |
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Footnotes |
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Received March 17, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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