Bull Vet Inst Pulawy 51, 37-42, 2007
NON-GENOMIC EFFECT OF OVARIAN STEROIDS
ON OXYTOCIN-STIMULATED PROSTAGLANDIN (PG) F2α
AND E2 SECRETION
FROM BOVINE ENDOMETRIAL CELLS
MAGDALENA KOWALIK, AND JAN KOTWICA
Institute of Animal Reproduction and Food Research, Polish Academy of Sciences,
10-718 Olsztyn-Kortowo, Poland
[email protected]
Received for publication September 01, 2006.
Abstract
The aim of the study was to establish the effect of the
ovarian steroids: 17β-oestradiol (E2) and testosterone (T4) on
OT-stimulated PGF2α and PGE2 secretion by bovine
endometrial cells. The epithelial endometrial cells from days
14-18 of the oestrous cycle (105/ml) were incubated in
DMEM/Ham’s F12 with 10% FCS (38°C, atmosphere of air
and 5% CO2) for 72-96 h and the last 24 h in DMEM/Ham’s
F12 with 0.1% BSA. In Exp.1, the doses of steroids used to
study their effect on the secretion of PGF2α and PGE2 from
endometrial cells stimulated by OT were determined. In Exp.2,
the cells were pre-incubated for 30 min with selected doses of
steroids: P4 (10-5 M), T4 (10-5 M), and E2 (10-8 M) and next for
4 d with: arachidonic acid (AA; 10-5 M), OT (10-7 M) and OT
with each of these steroids. The concentration of PGE2 and
PGFM -metabolite of PGF2α was determined by EIA. P4, T4,
and E2 did not affect (P>0.05) the basal secretion of PGF2α
and PGE2, but all the steroids inhibited (P<0.01) OTstimulated PGF2α secretion. The stimulating effect of OT on
PGE2 secretion was not affected by P4 and T4 (P>0.05). This
data suggests that different cellular mechanisms exist for
steroids affecting the secretion of both prostaglandins from
endometrial cells. Moreover, we suggest that non-genomic
effect of P4 on bovine endometrial cells is non-specific since
the other steroids can impair the effect of OT on these cells.
This effect of the steroids can directly modulate function of
endometrial cells.
Key words: cows, non-genomic effect,
progesterone, steroids, endometrium, prostaglandins.
Prostaglandins (PGs) produced in the uterus,
are key mediators of several female reproductive
functions, including ovulation, luteolysis, fertilization,
implantation, and parturition (11, 17, 39). Recognition
and establishment of pregnancy involves several
molecular and cellular interactions between conceptus,
uterus, and corpus luteum (4). During the bovine
oestrous cycle, days 15-17 are crucial for the initiation
of luteolysis or maternal recognition of pregnancy (31,
34, 50). At this time, endometrial PGF2α is released in a
pulsatile manner (31, 45), while PGE2 acts as
luteotropic/antiluteolytic factor preventing luteolysis
during early pregnancy (1, 40).
Ovarian steroids play an important role in the
regulation of uterine PGs secretion in cattle (17).
Progesterone (P4) and oestrogens may directly affect the
basal PGF2α secretion by the endometrium (2, 52).
Moreover, these steroids can regulate the endometrial
responsiveness to oxytocin (OT) and to other regulatory
factors, and further OT stimulates PGF2α and PGE2
secretion from endometrial cells of cow (2, 23, 49).
Progesterone, which is produced in the corpus
luteum (CL), affects the timing of oestrous cycle and
pregnancy duration in many species, including cattle.
Although at the 10-12 d period, high concentration of P4
is essential for the uterus to achieve the ability to
synthesise PGF2α, it was shown that P4 decreases the
ability of OT-stimulated PGF2α secretion from bovine
endometrial cells and this is effected partly via a nongenomic mechanism (6, 18). The non-genomic action of
steroids was found in a number of tissues including the
female reproductive tract (18, 30, 44, 46), but the nature
of this mechanism is unknown. It is suggested that P4
may directly inhibit the binding of OT to its receptors in
endometrial cells, as observed earlier (5, 6, 12, 18), or it
can bind its specific membrane receptor (8, 35, 41, 42),
and next it can directly affect enzyme activity (46). It is
also possible that non-genomic effect of P4 is nonspecific, and other steroids such as lipophilic substances,
can change permeability of the cell membrane and in
this way affect the affinity of other membrane receptors
to their ligands (15, 16).
Recently, we have found that P4, its precursor
pregnenolone
(P5),
and
metabolite
17βhydroxyprogesterone (17βOHP4) suppressed the
influence of OT on the secretion of PGF2α, but not
PGE2, from endometrial cells (13). This inhibitory
effect appeared after short-term culture, which was not
sufficient to activate genomic pathway.
38
Therefore, the aim of present study was to
investigate whether other steroids: 17β-oestradiol (E2)
and testosterone (T4) can affect in non-genomic way the
secretory function of OT-stimulated bovine endometrial
cells.
Material and Methods
Tissue collection. Uteri were collected at the
commercial slaughterhouse from heifers and nonpregnant cows on days 14-18 of the oestrous cycle
within 1 h from slaughter, and transported to the
laboratory in ice-cold PBS. The stage of the oestrous
cycle was assessed by morphological observations of the
reproductive tract (20). Uteri from 4 to 6 animals were
collected for each experiment and each treatment was
done in 4 repetitions. All materials used in these studies
were obtained from Sigma (Poland) unless otherwise
stated.
Isolation of endometrial epithelial cells.
Endometrial epithelial cells from the horn ipsilateral to
CL were isolated according to Skarżynski et al. (48)
with some modifications (13). The number of cells and
cell viability were determined by means of 0.04% trypan
blue exclusion. Cells with viability above 80% were
only used.
Experiment 1. The purpose of this experiment
was to determine the doses of steroids used to study
their effect on the secretion of PGF2α and PGE2 from
endometrial cells stimulated with OT. Dispersed
endometrial epithelial cells (105) were suspended in
DMEM/Ham’s F12 with 10% FCS and 20 µg/ml of
gentamycin into each of 48-well plates (Nunc GmbH &
Co. KG, Germany), and incubated (Heraus BB-6060,
Germany) at 38°C in a humidified atmosphere (95% of
air and 5% of CO2). The medium was changed after 48
and 72 h, and after 96 h if necessary, in order for cells to
attach to the bottom of the well. Then the cells were
incubated in a medium DMEM/Ham’s-F12, containing
0.1% BSA and 20 µg/ml of gentamycin for 24 h.
Subsequently, the medium was replaced with a fresh one
and the cells were pre-incubated for 30 min with: P4
(10-7, 10-6, 10-5 M), T4 (10-7, 10-6, 10-5 M), and E2 (10-9,
10-8, 10-7 M). Then, the medium was supplemented with
arachidonic acid (AA; 10-5 M) as the positive control,
OT (10-7 M) and OT with each dose of the steroid. The
cells were incubated for 4 h; and thereafter, the medium
was added to the tubes containing 10 µl of mixture (30
µM EDTA, 1% acetylsalicylic acid), and stored (-20°C)
until analysis of PGE2 and PGF2α metabolite – PGFM
concentrations. PGFM concentration reflects 50% of
PGF2α secretion by the endometrium as reported earlier
(47); hence, both these terms are used in this paper.
Experiment 2. Based on the data from Exp.1,
endometrial epithelial cells (105) were pre-incubated
with the selected doses of steroids (a) P4 (10-5 M), (b) T
(10-6M), (c) E2 (10-8 M), for 30 min. Next, the cells were
incubated with AA (10-5 M), OT (10-7 M) and OT,
together with the mentioned steroids for 4 h. After the
end of incubation, the medium was collected for the
determination of PGFM and PGE2 concentrations.
Protein concentrations in cells were measured by the
Bradford method (7), and the hormone concentrations
were expressed per milligrams of protein.
Hormone assays. Concentrations of PGFM
were determined directly in the medium by enzyme
immunoassay (EIA) using horseradish peroxidaselabelled PGFM as a tracer (1: 40 000; final dilution) and
anti-PGFM serum (1: 80 000) characterised earlier (19).
The standard curve ranged from 62.5 to 32 000 pg/ml.
The intra- and inter-assay coefficients of variation were
13.4% and 16.4%, respectively.
PGE2 concentrations were determined also by
EIA, using horseradish peroxidase-labelled PGE2 (1: 30
000; final dilution) and anti-PGE2 serum (diluted 1: 80
000). The standard curve ranged from 78 do 20 000
pg/ml. The intra- and inter-assay coefficients of
variation were 5.75% and 11.3%, respectively.
Data analysis. Due to the variation of data
obtained in Exp.1, PGFM and PGE2 concentrations
were expressed as percentages and compared to control
values accepted as 100%. Analysis of the data was made
by using ANOVA and Newman-Keuls as post-test
(PRISM, GraphPad Software, USA), row values were
transformed to logarithms (base 10) to ensure
homogeneity of variance. Mean (±SEM) concentrations
of PGFM and PGE2 in Exp.2 were analysed by
ANOVA and a Newman-Keuls as the post-test.
Results
Experiment 1. Not all the doses of P4 affected
the basal secretion of PGFM from bovine endometrial
cells on days 14-18 of the oestrus cycle (Fig. 1a).
However, P4 in the doses of 10-6 M and 10-5 M
decreased (P<0.05) OT-stimulated effect on PGFM
concentrations (Fig. 1a). Testosterone in all used doses
increased (P<0.05) PGFM concentrations (Fig. 1b) and
in the doses of 10-5M and 10-6 M decreased (P<0.001)
the stimulating effect of OT (Fig. 1b). Oestradiol in 10-8
M dose (P<0.01) stimulated basal concentration of
PGFM (Fig. 1c) and the doses of E2 (10-8 M- 10-7 M)
abolished (P<0.001) the effect evoked by OT on PGFM
concentration (Fig. 1c). Only T4 (Fig. 1e) increased
(P<0.05), but other steroids did not affect (P>0.05) the
basal secretion of PGE2 (Figs 1d, 1f). There was
observed inhibitory effects of the used steroids on OTstimulated PGE2 secretion (P>0.05) (Figs 1d, 1e, 1f).
Experiment 2. Both AA (positive control) and
OT stimulated (P<0.01-0.001) the secretion of PGFM
(Fig. 2) and PGE2 (Fig. 3). Any of the steroids used
affected basal secretion of both prostaglandins (Figs 2,
3). However, all the steroids inhibited (P<0.05) OT
effect on PGFM secretion from endometrial cells
collected on days 14-18 of the oestrous cycle (Fig. 2).
P4 and T4 did not affect (P>0.05) OT-stimulated PGE2
secretion (Fig. 3), but E2 decreased the stimulatory
influence of OT.
39
c
PGFM (%)
400
160
120
9000
(a)
b
b
a
a
a
a
a
a
80
40
C
AA
OT 10
10
-6
10
-5
10
-7
P4
500
PGFM (%)
10
-6
10
b
cd
C
AA
OT 10-7 10-6 10 -5 10-7 10 -6 10-5
P4+OT
d
(e)
6000
200
c
cd
a
ad
b
bc
150
100
bc
bc
c
bc
bc
a
50
C
500
0
OT 10-7 10-6 10 -5 10-7 10-6 10 -5
AA
C
AA
T4
9000
(c)
b
ac
d
ac
T4+OT
c
(f)
6000
200
ab
cd
80
40
PGE2 (%)
b
b
OT 10-7 10-6 10 -5 10-7 10 -6 10-5
T4+OT
e
400
160
PGFM (%)
bc
ac
P4
(b)
b
c
T4
0
ac
a
9000
40
120
100
ab
ac
P4+OT
80
0
b
150
0
-5
e
400
160
120
(d)
b
50
-7
PGE2 (%)
0
d
6000
200
PGE2 (%)
500
b
150
100
ab
a
ab
ab
ab
ab
a
50
C
AA
OT
10-9 10-8 10-7 10-9 10-8 10-7
E2
0
C
AA
OT
10-9 10 -8 10-7 10 -9 10-8 10 -7
E2
E2+OT
E2+OT
Fig. 1. Mean (±SEM) concentrations of PGFM (a-c) and PGE2 (d-f) in medium incubated with endometrial cells on days 14-18 of
the oestrous cycle of the cows (n=6). The cells were pre-incubated for 30 min with different doses of progesterone (P4; 10-7, 10-6, 105
M), testosterone (T4; 10-7, 10-6, 10-5 M), oestradiol (E2; 10-9, 10-8, 10-7 M), and next incubated 4 h with: arachidonic acid (AA; 10-5
M), oxytocin (OT; 10-7 M), and OT together with each dose of the steroid. Values were compared to controls (100%). Bars with
different superscripts are different (P<0.05-0.001).
(a)
400
300
b
200
1000
500
400
OT
P4
P4+OT
c
1500
PGFM (pg/mg protein)
AA
(b)
b
a
a
a
300
200
PGE2 (pg/mg protein)
C
0
C
1500
AA
OT
T4
(c)
1000
500
400
b
a
ac
300
c
200
600
C
AA
OT
E2
E2+OT
Fig. 2. Mean (±SEM) secretion of PGFM by uterine epithelial
cells on days 14-18 of the oestrous cycle of the cows (n=4-6).
The cells were pre-incubated for 30 min with: (a) progesterone
(P4; 10-5M), (b) testosterone (T4; 10-6 M), (c) oestradiol (E2;
10-8 M) and next incubated 4 h with: arachidonic acid (AA;10-5
M), oxytocin (OT; 10-7 M), and OT together with each of the
steroid. Bars with different superscripts are different (P<0.050.001).
b
a
a
400
200
C
AA
OT
(b)
b
1500
1000
P4
P4+OT
c
15000
10000
2000
b
a
a
500
C
AA
OT
T4
T4+OT
c
(c)
10000
1200
b
1000
800
600
a
a
a
400
200
0
100
0
800
15000
T4+OT
d
(a)
b
1000
0
100
c
10000
1200
0
100
0
PGFM (pg/mg protein)
a
a
a
PGE2 (pg/mg protein)
PGFM (pg/mg protein)
c
1000
500
PGE2 (pg/mg protein)
15000
1500
C
AA
OT
E2
E2+OT
Fig. 3. Mean (±SEM) secretion of PGE2 by uterine epithelial
cells on days 14-18 of the oestrous cycle of the cows (n=4-6).
The cells were pre-incubated for 30 min with: (a) progesterone
(P4; 10-5 M), (b) testosterone (T4; 10-6 M), (c) oestradiol (E2;
10-8 M) and next incubated 4 h with: arachidonic acid (AA; 105
M), oxytocin (OT; 10-7 M), and OT jointly with steroids.
Bars with different superscripts are different (P<0.05-0.001).
40
Discussion
Secretion of oxytocin-stimulated PGF2α, but
not that of PGE2, is suppressed in the dose dependent
manner by P4, E2, and T4 in endometrial cells from
days 14-18 of the oestrous cycle. This inhibitory effect
appears after short-term culture (4 h), so this effect of
steroids cannot be mediated through genomic
mechanism,
either
activating
or
suppressing
transcription of specific genes. These data suggest that
P4, T4, and E2 inhibited OT-stimulated PGF2α
secretion in a non-genomic way as reported earlier (6,
18), but the nature of this mechanisms is still unknown.
It was found that P4, E2, and T4 can affect cell
function by membrane receptors in many tissues (8, 14,
30, 35-38, 41-43, 46). Thus, it is possible that the
studied steroids can bind their membrane receptors or
can impair binding of OT to its membrane receptors, as
observed before for P4 (5, 6, 12, 18). However, this
effect of P4 on OT receptors was not confirmed by
others who used human and bovine tissues (3, 9, 21). It
is also suggested that P4, as a lipophilic substance, can
change permeability of cell membrane, and in this way
can temporarily impair structure of membrane receptors
(46). The effect of steroids on membrane fluidity was
not studied; however, it cannot be excluded that they
affect OT influence in this way, or they can influence
the concentration of cholesterol in the cell membrane, as
suggested earlier (15, 16). It has been showed that
cholesterol stabilises the human OT receptor and causes
its high affinity to the ligand (24). Progesterone could
inhibit the signal transduction of G-protein-coupled
receptors and the intracellular transport of cholesterol
(16). Thus, the effect evoked by P4 is very transient as it
was showed using epithelial and stromal cells from
bovine endometrium (2). This mechanism of P4
influence upon endometrial cells, affected the release of
calcium, which plays an important role in mediating the
stimulatory effect of OT on PGF2α secretion by the
bovine endometrium (10).
However, explanation of the mechanism for the
effect on the steroids we used in this study is more
complicated since there is no data to its affect on
cholesterol transport or its production from precursors. It
has been proposed that rapid, non-genomic action of E2,
T4, and other steroids may be exerted through plasma
membrane receptors that stimulate early intracellular
signalling pathways, which involves interaction with G
proteins (22, 33, 46, 51). Recently, we found that P4, P5
and 17βOHP4 impaired OT-stimulated PGF2α secretion
from endometrial cells and decreased intracellular
mobilisation of Ca2+ in response to OT challenge (13).
Machelon et al. (30) showed that P4 induced calcium
mobilisation from the endoplasmic reticulum of
granulosa cells. Moreover, both the nuclear P4 receptor
antagonist (RU-38486) and P4 immobilised on bovine
serum albumin, which did not enter the cell, also
increased Ca2+ mobilisation within 5 s. The authors
assume this effect is via the activation of membrane
receptors, that belong to the class of membrane
receptors, coupled to the phospholipase C and that this
process is controlled by protein kinases C and A.
Whether other steroids we used in these studies also
affect Ca2+ release via the same mechanism is not
known.
Cow endometrial epithelial cells in vitro secrete
both prostaglandins (F2α and E2) and these cells are
mainly responsible for the regulation of PGs synthesis
by sex steroids and OT (2). The OT response is limited
to epithelial endometrial cells as shown earlier (2, 23),
so the prostaglandins were secreted from epithelial cells.
In our studies, OT stimulated PGF2α and PGE2
secretion by dispersed endometrial cells from late luteal
stages of the oestrous cycle. These data confirmed
previous reports (2, 6, 23, 28). Although OT is not
essential as a trigger for luteolysis in cattle (25, 26), it
may regulate the amplitude of pulsatile PGF2α secretion
after initiation of luteolysis (27). Ovarian steroids can
directly affect the basal PGF2α and PGE2 secretion by
the endometrium, and, in turn, they can regulate the
responsiveness to OT and to other regulatory factors (2,
17, 52). However, E2 did not stimulate PGF2α release
by bovine endometrial tissue in short-term culture
without P4 pre-treatment (28, 47). Thus, P4 priming is
necessary to induce the responsiveness of the bovine
uterus to oestradiol and OT (28, 29, 47). Therefore, it
can be accessed that P4 directly affects PGF2α synthesis
in the bovine uterus, but E2 can only modulate this
process.
The previous studies (13) revealed that P4 and
T4 did not affect basal secretion of PGF2α, but inhibited
OT-stimulated PGF2α secretion from endometrial slices
and dispersed cells. Moreover, P4 and E2 decreased OT
effect on myometrial cells (32). In the present study P4,
E2, and T4 affected OT-stimulated secretion of PGF2α,
but not that of PGE2. This suggests that different
cellular mechanisms exist for steroids affecting secretion
of both prostaglandins from epithelial cells. There is no
clear explanation for this phenomenon, but one
possibility is that the reduction in the Ca2+ response may
affect critical enzymes that control the PGE2 to PGF2α
ratio (13).
It is suggested also that this inhibiting influence of
steroids may temporarily modify or impair the binding
of OT to its membrane receptors, and in this way can
limit the effect OT on the cells. This influence of the
steroids can directly modulate function of endometrial
cells and supposedly of others.
Our results indicate that non-genomic pathway
of steroids influence on target cell can inhibit the
secretion of luteolytic PGF2α and in this way may
support action of PGE2, which has luteotropic
properties. This effect may support CL function and in
this way protect pregnancy against luteolytic influence
of PGF2α. Arosh et al. (1) showed that the recognition
and establishment of pregnancy in cattle may depend not
only on the inhibition of endometrial PGF2α, but also on
increase of PGE2 production. Therefore, it is possible
that this non-genomic effect of steroids on endometrial
PGF2α and PGE2 secretion is one more mechanism able
to protect an early pregnancy.
41
Acknowledgments: We thank Professor W.W.
Thatcher (University of Florida, USA) for supplying
PGE2 antisera and Professor W.J. Silvia (University of
Kentucky, USA) for supplying PGFM antisera This
work was supported by the State Committee for
Scientific Research (grant 2P06K 038 29) and by the
Polish Academy of Sciences. Part of these results was
already presented earlier (PTHC Meeting, Stare
Jabłonki, 2006).
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