Journal of Reproduction and Development, Vol. 46, No.

2, 2000

Basic Fibroblast Growth Factor-Induced Prostaglandin

Production and Its Intracellular Mechanisms in Cultured Bovine
Luteal Cells
Yoshihisa UENOYAMA, Shuko MURAKAMI, Dieter SCHAMS1) and
Kiyoshi OKUDA

Laboratory of Reproductive Endocrinology, Okayama University,

Okayama 700–8530, 1)Institute for Physiology, Technical University of Munich,
85350 Freising-Weihenstephan, Germany

Abstract. The effect of basic fibroblast growth factor (bFGF) on the production of prostaglandin
(PG) F2α and PGE2, and the intracellular mechanisms of its action, were investigated in cultured
bovine mid-luteal cells (days 8–12 of the estrous cycle). The cells were cultured for 24 h and then
exposed to varying concentrations of bovine recombinant bFGF (rbFGF, 1–100 ng/ml) for a further
24 h. A 24-h stimulation with the highest concentration of rbFGF resulted in increases in both
PGF 2α and PGE 2 production by mid-luteal cells (P<0.05). Both U-73122 (an inhibitor of
phospholipase (PL) C, 10–6 M) and anthranilic acid (ACA; an inhibitor of PLA2, 10–6 M) inhibited the
rbFGF-induced PGF2α and PGE2 production (P<0.05). Moreover, following down-regulation of
protein kinase C with a tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA,
10–6 M), the stimulatory effect of rbFGF was no longer evident. These results suggest that locally
produced bFGF may play a role as one of the autocrine and/or paracrine stimulators of the
production of PGs in bovine corpus luteum, and the stimulatory effect of bFGF on the production
of PGs is mediated via the PLC-PKC-PLA2 pathway.
Key words: Basic fibroblast growth factor, Cow, Corpus luteum, Prostaglandins, Phospholipases.
(J. Reprod. Dev. 46: 93–99, 2000)

any peptide growth factors have a much
wider range of action than the biological
activity for which they were originally named [1].
For instance, basic fibroblast growth factor (bFGF)
was originally identified as a stimulator of the
proliferation of fibroblasts [2]. However, it is now
well known that bFGF is involved in angiogenesis
in a number of different tissues. This peptide has
been identified in a wide range of highly
vascularized tissues, including the bovine corpus
luteum (CL) [3]. It stimulates proliferation of luteal
vascular endothelial cells in vitro [4], and is
Accepted for publication: January 7, 2000
Correspondence: K. Okuda
produced in cultured bovine granulosa cells [5] and
luteal cells [6]. These observations have led to the
suggestion that bFGF is a major angiogenic factor
in the bovine CL. In addition to the angiogenic
action, it has also been demonstrated that bFGF is
involved in the regulation of steroidogenesis and
oxytocin secretion from the microdialyzed bovine
CL [7, 8].
It has been shown that the bovine CL produces
prostaglandins (PGs) as well as steroids and
peptides [9, 10]. Although PGs play roles as
autocrine and/or paracrine regulators in the bovine
CL [11–13], the factors that regulate their
production are not clearly understood. It has been
reported that bFGF enhances the production of PGs
94 UENOYAMA et al.
in many types of cells, such as Syrian hamster
embryo fibroblasts [14], synovial cells [15], mouse
osteoblasts [16], rabbit chondrocytes [17] and rat
luteal cells [18]. The aim of the present study was,
therefore, to investigate the possible action of bFGF
on the production of PGs, and the intracellular
mechanism of its action in cultured bovine luteal
cells.
Materials and Methods
Collection of CL
Ovaries with CL were collected from Holstein
cows at a local abattoir within 10–20 min after
exsanguination. The luteal stage was classified as
early stage (5–6 days after ovulation), mid-stage
(8–12 days after ovulation) and late stage (15–18
days after ovulation) by macroscopic observation
of the ovaries as described previously [19]. The
ovaries were submerged in ice-cold physiological
saline containing antibiotics before being
transported to the laboratory.
Tissue dissociation and cell preparation
A slight modification of the two-step perfusion
procedure previously described by Okuda et al.
[20], was used for the dissociation of the CL. Briefly,
CL were perfused with ethylglycol-bis-( β -
aminoethyl)-N,N,N’,N’-tetraacetic acid (EGTA)
buffer (0.1 mM EGTA (Sigma Chemical Co., St.
Louis, MO, E4378), 10 mM HEPES (Sigma, H0763),
140 mM NaCl, 7.1 mM KCl; pH 7.4) for 15 min
and wash buffer (10 mM HEPES, 140 mM NaCl,
7.1 mM KCl, 5 mM CaCl2; pH 7.4) containing 0.05%
collagenase (Sigma, C0130) and 0.1% bovine serum
albumin (BSA; Boehringer Mannheim GmbH,
Mannheim, Germany, 735078) for 30 min. The
treated luteal tissues were dissociated from the CL
matrix with steel combs. The dissociated tissues
were then enzymatically dispersed with 0.05%
collagenase and 0.005% deoxyribonuclease I
(Sigma, D5025). The cells were then filtered
through metal meshes (150 µm and 80 µm), and
washed three times by centrifugation for 5 min at
150 × g, decanted, and resuspended in Dulbecco’s
Modified Eagle’s Medium (Sigma D1152). After
three washes, the cells were resuspended in culture
medium, Dulbecco’s Modified Eagle’s Medium and
Ham’s F-12, 1:1 (vol/vol; DME/F-12; Sigma, D8900)
supplemented with 5% calf serum (CS; Sigma,
C6278) and 20 µ g/ml gentamicin (Gibco BRL,
Grand Island, NY, 15750–060). Cell viability was
higher than 85% as assessed by trypan blue
exclusion. Cell suspensions contained very few
endothelial cells and/or fibrocytes (0–10%) and no
erythrocytes.
Cell culture
The dispersed luteal cells were seeded at 1 × 105
viable cells/0.5 ml, in 48-well cluster dishes (Costar,
Cambridge, MA, 3524) and cultured in a
humidified atmosphere of 5% CO2 in air at 37.5 C.
Twenty-four hours after the start of culture, culture
media were replaced by fresh culture medium
containing 5% CS and 20 µg/ml gentamicin. The
cells were then exposed to bovine recombinant
bFGF (rbFGF; kindly donated by Dr. D.
Gospodarowicz, Chiron Corporation, Emeryville,
CA).
To determine the effective dose and exposure
time of rbFGF on PGF2α production, mid-luteal cells
were exposed to varying concentrations of rbFGF
(1–100 ng/ml) for 2, 4, 8 or 24 h. Moreover, cycle-
dependent changes of luteal PGF2α production in
response to rbFGF (100 ng/ml) were examined.
Finally, to evaluate the intracellular mechanisms
of rbFGF action, the cells were exposed to a
phospholipase (PL) C inhibitor (U-73122;
Calbiochem, San Diego, CA; 662035; 10–6 M), a PLA2
inhibitor (anthranilic acid, ACA; Calbiochem;
104550; 10–6 M) and/or rbFGF (100 ng/ml) in the
final 24 h of culture. The effects of rbFGF on the
production of PGs by intact and protein kinase C
(PKC)-deficient luteal cells were also compared.
PKC-deficient cells were produced by
preincubating the cells with chronic exposure to
phorbol 12-myristate 13-acetate (PMA; Sigma,
P8139; 10–6 M) before rbFGF stimulation [12, 13,
21].
At the end of each experiment, the conditioned
media were collected in tubes with 5 µl of stabilizer
(0.3 M EDTA, 1% Aspirin (Sigma, A2093), pH 7.3),
and stored at −30 C until assayed for PGF2α and
PGE 2. The DNA content was estimated by a
spectrophotometric method as described by
Labarca and Paigen [22] at the end of the culture
period. DNA content did not vary across
treatments, suggesting that the number of cultured
luteal cells was not affected by any treatments used
in the present study.
 EFFECT OF bFGF ON CL AND INTRACELLULAR SIGNAL 95

Hormone determination
The concentration of PGF 2α was determined
directly in the conditioned media by enzyme
immunoassay (EIA) as described previously [23].
The PGF2α standard curve ranged from 15.6 to 4000
pg/ml, and the ED50 of the assay was 200 pg/ml.
The intra- and interassay coefficients of variation
were 8.1% and 11.6%, respectively.
PGE2 concentration was also determined directly
with an EIA as described previously [24]. The PGE2
standard curve ranged from 0.39 to 100 ng/ml,
and the ED 50 of the assay was 2.8 ng/ml. The
intra- and interassay coefficients of variation were
3.7% and 7.4%, respectively.

Statistical analysis
The data are shown as the mean ± SE of values
obtained from separate experiments each
performed in triplicate. The statistical significance
of differences between the control and treated
groups was assessed by an analysis of variance
followed by Fisher’s protected least significant
difference procedure as a multiple comparison test
(StatView; Abacus Concepts, Inc., Berkeley, CA).
For the statistical analyses of differences in the
production of PGs, the relative percentages of the
control were used.
Results
Figure 1A shows the time-dependent effects of
rbFGF on PGF2α production by cultured bovine
mid-luteal cells. Although rbFGF (100 ng/ml) had
no effect on PGF2α production after 2, 4 or 8 h of
incubation, PGF 2α production increased
significantly after 24-h incubation (P<0.05).
Moreover, when the cells were exposed to varying
concentrations of rbFGF (1–100 ng/ml) for the final
24 h of culture, PGF2α production increased from
122% to 134% of the controls with increasing
concentrations of rbFGF from 10 to 100 ng/ml
(P<0.05, Fig. 1B). The stimulatory effect of rbFGF
on PGF 2α production was observed in all three
luteal stages, whereas the amount of PGF 2α
production was lower in cultured luteal cells of
the late luteal stage than in cultured luteal cells of
the early and mid-luteal stages (Table 1).
In addition to PGF 2α production, rbFGF
stimulated PGE2 production by cultured mid-luteal
Fig. 1. Time- and dose-dependent effects of rbFGF on
PGF2α production by cultured bovine mid-luteal
cells (mean ± SE). A) Twenty-four hours after
the start of culture, the cells were exposed to 100
ng/ml rbFGF for 2, 4, 8 or 24 h (n=3). B) The
cells were exposed to rbFGF (1–100 ng/ml) in
the final 24 h of culture (n=5). All values are
expressed as a percentage of the value of the
untreated control. The concentration of PGF2α in
the controls was 697 ± 47 pg/ml. Asterisks
indicate values significantly higher than the
control (P<0.05) and different letters indicate
significant differences (P<0.05), as determined
by ANOVA followed by Fisher’s PLSD.
cells (P<0.05, Figs. 2, 3). On the other hand, U-
73122 (a PLC inhibitor) and ACA (a PLA2 inhibitor)
completely suppressed the stimulatory effect of
rbFGF on PGF2α and PGE2 production (P<0.05, Fig.
2). Moreover, the PKC-deficient luteal cells secreted
a similar amount of PGF2α and PGE2 compared
with intact luteal cells (P>0.05). However, PGF2α
and PGE2 production by the PKC-deficient luteal
cells were not affected by the exposure to rbFGF
(P>0.05, Fig. 3).
96 UENOYAMA et al.

Table 1. Effect of rbFGF on PGF2α production by cultured bovine luteal

cells during the estrous cycle (mean ± SE, n=3)

PGF2α secretion (pg/ml) during the estrous cycle

Treatment Early Mid- Late
Control 682 ± 72a 789 ± 96a 213 ± 10b
rbFGF 893 ± 59* 1084 ± 67* 312 ± 20*
Luteal cells were exposed to rbFGF (100 ng/ml) in the final 24 h of culture.
Different superscript letters indicate significant differences among the stages
of the estrous cycle (P<0.01) and asterisks indicate that bFGF had a signifi-
cant effect on PGF2α production in each stage of the estrous cycle (P<0.01),
as determined by ANOVA followed by Fisher’s PLSD.

Fig. 2. Effects of a PLC inhibitor (U-73122) and a PLA2
inhibitor (ACA) on rbFGF-induced A) PGF 2α
and B) PGE 2 production by cultured bovine
luteal cells (mean ± SE, n=3). The cells were
exposed to each inhibitor alone (10–6 M) or in
combination with rbFGF (100 ng/ml) in the
final 24 h of culture. All values are expressed
as a percentage of the value of the untreated
control. The concentrations of PGF2α and PGE2
in the controls were 606 ± 25 pg/ml and 32 ±
7 ng/ml, respectively. Asterisks indicate values
significantly higher than the control (P<0.05), as
determined by ANOVA followed by Fisher’s
PLSD.
Fig. 3. Effects of rbFGF on A) PGF 2α and B) PGE 2
production by intact or PKC-deficient luteal
cells (mean ± SE, n=3). The cells were exposed
to rbFGF (100 ng/ml) for 24 h following 24 h
preincubation with 10–6 M phorbol 12-myristate
13-acetate (PMA; PKC-deficient cells) or 0.1%
DMSO (diluent for PMA; Intact cells). All
values are expressed as a percentage of the
value of the untreated control in intact cells.
The concentrations of PGF2α and PGE2 in the
controls were 667 ± 36 pg/ml and 28 ± 6 ng/
ml, respectively. Asterisks indicate values
significantly higher than the control (P<0.05),
as determined by ANOVA followed by Fisher’s
PLSD.
 EFFECT OF bFGF ON CL AND INTRACELLULAR SIGNAL
Discussion
The present study clearly demonstrated that
rbFGF increased the production of PGF2α and PGE2
by cultured bovine luteal cells. Treatment for 24 h
with rbFGF had no effects on cell number (data
not shown), suggesting that the stimulative effect
of rbFGF can not be attributed to an increase in
cell number. In our previous study, we detected
the specific binding sites for 125I-labeled bFGF in
cultured bovine luteal cells at all three luteal stages
of the oestrous cycle [25]. The concentrations of
rbFGF (10–100 ng/ml) that increased the
production of PGs are consistent with the affinities
of bFGF receptors in bovine luteal cells (Kd=9.9
nM: approximately 178 ng/ml) [25] and in rat luteal
cells (Kd=0.19–0.24 nM: approximately 4 ng/ml)
[26] reported previously. In view of the above
findings, we assume that the stimulatory effects of
rbFGF on the production of PGs are mediated by
bFGF-specific receptors present on bovine luteal
cells.
It has been well demonstrated that the
production rate of PGs in bovine CL are cycle-
dependent [9, 10]. In the present study, the amount
of PGF2α production was lower in cultured luteal
cells of the late luteal stage than in those of the
early or mid-luteal stage. The stimulatory effect of
rbFGF on PGF2α production is, however, similar in
all three luteal stages. The present result is
consistent with our previous results that the
concentrations and affinities of bFGF receptors in
bovine CL remain the same throughout the luteal
stages [25]. Since bFGF mRNA is expressed in
bovine CL [6] and the peptide is produced
throughout the luteal stages [27], locally produced
bFGF might play a significant role as a paracrine
and/or autocrine factor in the regulation of the
production of PGs in bovine luteal cells throughout
the luteal stages. The intraluteal PGs are known
to be luteotropic agents in cultured luteal cells as
well as microdialyzed bovine CL [11, 12].
Therefore, we postulate that bFGF indirectly plays
a role in progesterone production by stimulating
PG production in bovine CL. However, the
stimulatory effects of bFGF on the production of
PGs were significant, but not very strong. Thus,
bFGF may play a role in PG production as a
complementary modulator with other factor(s). In
fact, a synergistic effect between interleukin-1β and
97
bFGF on PG production has been observed in rabbit
articular chondrocytes [28] or rheumatoid arthritis
synovial cells [29]. Further studies are, therefore,
needed to clarify the synergistic effect of bFGF and
other factor(s) in the bovine corpus luteum.
The receptors for most growth factors including
bFGF are identified as transmembrane tyrosine-
specific protein kinase. Binding of a ligand to the
extracellular domain of a receptor tyrosine kinase
induces oligomerization of the receptors, resulting
in increased interaction of cytoplasmic kinase
domains and receptor autophosphorylation by a
trans mechanism [30]. Intracellular substrates such
as PLCγ then associate with, and are
phosphorylated by, activated receptor tyrosine
kinases. In general, PLCγ catalyzes the breakdown
of a membrane phospholipid, phosphatidylinositol
bisphosphate, into two second messengers, inositol
1,4,5-triphosphate (IP3) and diacylglycerol [31]. IP3
releases calcium from intracellular stores and
diacylglycerol activates PKC. Both activated PKC
and a high concentration of intracellular Ca 2+
activate PLA2, which stimulates the intracellular
accumulation of arachidonic acid, a common
precursor of PGF2α and PGE2. In the present study,
therefore, we evaluated whether the PLC-PKC-
PLA2 pathway is involved in the stimulatory action
of bFGF on luteal PGF2α and PGE2 production. This
hypothesis is supported by the present results. Both
U-73122 (a PLC inhibitor) and ACA (a PLA 2
inhibitor) completely inhibited rbFGF-stimulated
PGF2α and PGE2 production. Furthermore, the
stimulatory effect of rbFGF was no longer evident
in the PKC-deficient luteal cells. These results
strongly suggest that the stimulatory effect of bFGF
on PG production in luteal cells is mediated via
the PLC-PKC-PLA2 pathway. Furthermore, it has
been demonstrated that bFGF acutely enhanced the
expression of mRNA for PG G/H synthase-2
(PGHS-2), which is the major enzyme regulating
the conversion of arachidonic acid to PGs, in Syrian
hamster embryo fibroblasts [14] and mouse
osteoblasts [16]. Since the 5' flanking region of the
PGHS-2 promoter containing the 371-bp proximal
to the transcription start site appears to contain
one or more major bFGF response element, the
stimulatory effect of bFGF on PG production may
involve de novo synthesis of PGHS-2 in bovine luteal
cells. However, it is not evident whether bFGF
stimulates the expression of PGHS-2 mRNA in
bovine luteal cells. Further studies are needed to
98 UENOYAMA et al.
clarify this point.
In conclusion, the stimulatory effect of rbFGF on
PGF 2α and PGE2 production observed in vitro
suggests that bFGF plays a role as an autocrine
and/or paracrine regulator in stimulation of PG
production in bovine CL, and that the bFGF action
is mediated via PLC-PKC-PLA2 pathway.
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The authors thank Dr. Seiji Ito of Kansai Medical
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