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B-Mediated X-Linked Inhibitor of Apoptosis Protein Expression Prevents Rat Granulosa Cells from Tumor Necrosis Factor 
-Induced Apoptosis
Reproductive Biology Unit and Division of Reproductive Medicine, Departments of Obstetrics and Gynecology and Cellular and Molecular Medicine, University of Ottawa, Loeb Health Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada K1Y 4E9
Address all correspondence and requests for reprints to: Benjamin K. Tsang, Ph.D., Loeb Health Research Institute, The Ottawa Hospital (Civic Campus), 1053 Carling Avenue, Ottawa, Ontario, Canada K1Y 4E9. E-mail: btsang{at}lri.ca
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF) in rat granulosa cells. Granulosa cells from equine
CG-primed immature rats were plated in RPMI 1640 medium containing 10%
FCS and subsequently cultured in serum-free RPMI in the absence or
presence of TNF (20 ng/ml), the protein synthesis inhibitor
cycloheximide (10 µM), and/or adenoviral Xiap sense or
antisense complementary DNA. TNF alone failed to induce granulosa
cell death, but in the presence of cycloheximide, it markedly increased
the number of apoptotic granulosa cells (as assessed by in
situ terminal deoxynucleotidyl transferase-mediated
deox-UTPbiotin end labeling and DNA fragmentation analysis).
Western analysis indicated that TNF alone increased the Xiap protein
level, a response significantly reduced by adenoviral Xiap antisense
expression. Down-regulation of Xiap expression by antisense
complementary DNA induced granulosa cell apoptosis, which was
potentiated by the cytokine. Inhibition of nuclear factor-
B
activation by N-acetyl-cysteine and SN50 suppressed Xiap
protein expression and enhanced apoptosis induced by TNF. The latter
phenomenon was readily attenuated by adenoviral Xiap sense expression.
In conclusion, these findings suggest that Xiap is an important
intracellular modulator of the TNF death signaling pathway in
granulosa cells. Its expression is regulated by the TNF via a
nuclear factor-B-mediated mechanism. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TGF) (7)].
Tumor necrosis factor- (TNF) is a pleiotropic cytokine that can
induce differentiation, proliferation, and apoptosis in many cell types
(8, 9). It is produced by rat and bovine granulosa cells
and oocytes (10, 11, 12, 13) and is an important regulator of
steroid hormone production and follicular development and atresia
(14). In addition, TNF has been shown to inhibit
ovarian cell viability and proliferation (14) and
counteract the blocking effect of FSH on spontaneous granulosa cell
apoptosis in cultured rat early antral follicles by inducing ceramide
production and activating the interleukin-1ß-converting
enzyme/ced-3-related cysteine protease death pathway
(15).
Two receptors, TNFR1 and TNFR2, have been identified in a variety of
TNF response cells (16, 17, 18). TNFR1 contains an
intracellular death domain, which is required for signaling pathways
associated with apoptosis and nuclear factor-B (NFB) activation.
NFB activation regulates the expression of genes involved in the
inflammatory response (19, 20) and in the prevention of
TNF-induced apoptosis, such as zinc finger protein A20
(21, 22, 23), members of the Bcl-2 family (24),
Bcl-2 homolog Bfl-1/A1 (25), and inhibitor of apoptosis
proteins (26, 27). In addition, TNF activates caspase-8
and -3 and induces apoptosis in TNF-sensitive cells, such as human
U937 tumor cells (28) and bovine endothelial cells
(29). In the mouse, TNF alone does not induce apoptosis
in cultured granulosa cells (30). However, treatment of
granulosa cells with the protein synthesis inhibitor cycloheximide
(CHX) potentiated Fas-mediated cell death, suggesting the presence of
endogenous inhibitors of the Fas signaling pathway in granulosa cells
(30). Although the rapid activation of NFB by TNF
has been demonstrated in a number of cell systems (31),
whether it is involved in either the pro- or antiapoptotic actions of
TNF in granulosa cells is unknown. Previous studies from our
laboratory have shown that X-linked inhibitor of apoptosis protein
(Xiap) expression is higher in granulosa cells of healthy follicles
than in those of atretic ones (5). However, the
physiological roles of Xiap in follicular development and atresia
remain unclear.
In the present studies we used an equine CG (eCG)-primed rat
granulosa cell culture system to examine whether 1) Xiap plays a role
in regulating granulosa cell apoptosis after TNF challenge, and 2)
NFB is involved in the regulation of Xiap expression by TNF. Our
studies demonstrate that Xiap plays an important regulatory role in
granulosa cell apoptosis and that TNF alone is incapable of inducing
this response. The inability of the cell to undergo apoptosis is due in
part to the induction of the antiapoptotic factor.
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Materials and Methods |
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-32P]dideoxy-ATP (3000 Ci/mmol), and
[
32P]deoxy (d)-ATP (30 Ci/mmol) were
obtained from Amersham Pharmacia Biotech (Arlington
Heights, IL). Medium RPMI 1640 and FCS were purchased from Life Technologies, Inc. (Burlington, Canada). Nitrocellulose
membrane, acrylamide (electrophoresis grade),
N,N'-methylene-bis-acrylamide, ammonium
persulfate, dithiothreitol (DTT), glycine, and protein assay kit were
purchased from Bio-Rad Laboratories, Inc. (Hercules, CA).
X-Ray films were obtained from Eastman Kodak Co.
(Rochester, NY). Positively charged slides were purchased from
Fisher Scientific (Probe On Plus, Nepean, Ontario,
Canada). Recombinant rat TNF was obtained from R\|[amp ]\|D Systems, Inc. (Minneapolis, MN). CHX was purchased from BDH Inc.
(Toronto, Ontario, Canada). SM50 and SN50 were obtained from
BIOMOL Research Laboratories, Inc. (Plymouth, PA). NFB
probe and T4 polynucleotide kinase were purchased from Promega Corp. (Madison, WI). Rabbit polyclonal antibodies against human
phosphorylated and total IB- were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Xiap antibody was a gift
from Dr. Eric LaCasse, ApoptoGen, Inc. (Ottawa, Canada).
Preparation and culture of rat ovarian granulosa cells
Immature female Sprague Dawley rats at 24–25 days of age were
injected with eCG (15 IU, sc) 24 h before the ovaries were
removed. The granulosa cells were collected by follicular puncture,
washed, and pelleted (200 x g; 5 min). Cells were
resuspended and plated for 24 h in RPMI 1640 with 10% FCS and
cultured in serum-free medium with adenoviral antisense or sense Xiap
complementary DNA (cDNA), CHX, and TNF for various durations. To
effectively block NFB activation, granulosa cells were pretreated
with either SN50 (15 min; SM50 as control) or NAC (1 h) before the
addition of TNF (20 ng/ml). At the end of the incubation period, the
cells were harvested by trypsinization [trypsin (05.%) and EDTA (5.3
mM)] and centrifugation (200 x
g; 5 min) for further analyses.
Viral infection
Granulosa cells were either infected with an adenoviral Xiap
sense cDNA [at a multiplicity of infection (MOI) of 5] or with
antisense cDNA (MOI = 40) for 24 h before the addition of
TNF. Control cells were infected with adenoviral LacZ, and the
infection efficiency, evaluated by X-galactosidase test, was
approximately 90%. Adenoviral expression vectors containing the
full-length sense and antisense Xiap cDNAs were prepared as previously
described (32).
Protein extraction and Western analysis
Cells were sonicated in a lysis buffer (pH 7.4) containing NaCl
(150 mM), SDS (0.1%), sodium deoxycholate (0.5%), Nonidet
P-40 (1%) in PBS, and protease inhibitors [PMSF (1 mM),
aprotinin (10 µg/ml), and sodium orthovanadate (1 mM)].
The sonicates were pelleted, and the supernatant was retained and
stored at -20 C. The protein content of the extracts was determined
with the DC Protein Assay Reagent (Bio-Rad Laboratories, Inc.). Samples were mixed with loading buffer, resolved by 12%
SDS-PAGE, and electrotransferred (30 V, overnight) onto nitrocellulose
membranes. After blocking for 1 h with nonfat milk powder (5%) in
Tris-buffered saline [Tris (10 mM) and NaCl (150
mM); TBS] and Tween-20 (0.05%; TBS-T), membranes were
incubated for 3 h with primary antibodies in TBS-T containing 5%
nonfat milk powder and subsequently with horseradish
peroxidase-conjugated secondary antibody (1:5,000–10,000) in TBS-T
with milk powder (room temperature, 45 min). Immunoreactivity was
detected by chemiluminescence autoradiography (ECL kit) in accordance
with the manufacturer’s instructions.
Electrophoretic mobility shift assay (EMSA)
Nuclear extracts of rat granulosa cells were prepared as
described previously by McKinsey et al. (33)
with minor modifications. Briefly, 3 x 106
cells were pelleted (200 x g; 5 min) and resuspended
in 30 µl buffer A [HEPES (10 mM; pH 7.9), KCl
(10 mM), MgCl2 (1.5
mM), DTT (0.5 mM), PMSF
(0.5 mM), and Nonidet P-40 (0.67%)]. Cells were
allowed to swell at 0 C for 15 min and were centrifuged at 10,000
x g at 4 C. The supernatant was extracted and stored at
-80 C. The cell pellet (containing cell nuclei) was resuspended in 30
µl buffer B [HEPES (20 mM; pH 7.9), NaCl (0.4
M), EDTA (0.2 mM),
MgCl2 (1.5 mM), DTT (0.5
mM), and PMSF (0.5 mM)]
and rocked vigorously (4 C, 15 min). The nuclear extract was
centrifuged (10,000 x g, 30 min) and stored at -80 C.
Double strand DNA oligonucleotides containing consensus sequences for
NFB were 32P labeled with
[32P]ATP and T4 polynucleotide kinase. Nuclear
proteins (8 µg) were incubated with radiolabeled DNA probes (room
temperature, 20 min) in the binding buffer. Nuclear acid-protein
complexes were resolved on a native 5% polyacrylamide gel in
Tris-buffered EDTA (1x; pH 8.0) and detected by autoradiography.
Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin end labeling (TUNEL). In situ cell death detection by the TUNEL technique was carried out as previously described (34). Fifty microliters of the cell suspension were placed on the positively charged slides, air-dried, fixed with formaldehyde (10%; 30 min), and immersed in methanol containing H2O2 (0.3%). After a 15-min rinse with distilled water, the slides were incubated in the TdT buffer [Tris-HCl (25 mM), sodium cacodylate (200 mM), cobalt chloride (5 mM), and BSA (250 µg/ml), pH 6.6, 15 min] and then in 50 µl TdT buffer containing TdT (10 U) and biotinylated dUTP (1 nmol) in a humidified chamber (37 C, 60 min). The biotinylated dUTP molecules incorporated into nuclear DNA were visualized with horseradish peroxidase-conjugated streptavidin (1:100; room temperature, 30 min) and DAB solution (room temperature, 5 min). At least 500 cells were counted in each experimental group.
DNA fragmentation analysis
DNA was extracted and labeled as previously described
(35). To 3'-end label DNA, DNA (1 µg) was incubated with
TdT (25 U) and [32P]dideoxy-ATP (5 µCi,
3000 Ci/mmol) in 50 µl sodium cacodylate (200 mM), cobalt
chloride (5 mM), BSA (250 µg/ml), and Tris-HCl (25
mM), pH 6.6, at 37 C for 60 min. The reaction was
terminated by the addition of 5 µl EDTA (250 mM; pH 8.0).
Unincorporated radionucleotides in the reaction mixture were removed
with the QIAGEN nucleotide removal kit (Chatsworth, CA).
The labeled samples were resolved by 1.8% agarose gel electrophoresis.
The gel was dried (3 h) and exposed to x-ray film at -80 C.
Statistical analysis
Results are expressed as the mean ± SEM of
three experiments. Statistical analyses were carried out by one- or
two-way ANOVA. Significant differences between treatment groups were
determined by the Tukey test. Statistical significance was inferred at
P < 0.05.
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Results |
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-induced apoptosis in the presence of CHX (20 ng/ml),
CHX (10 µg/ml), or CHX plus TNF. Treatment of cells with CHX had
no detectable effect on either apoptosis or Xiap protein level (Fig. 1
). TNF alone failed to induce
granulosa cell death, but in the presence of inhibitor it remarkably
increased the number of TUNEL-positive granulosa cells (Fig. 1A). DNA
fragmentation analysis showed that TNF-induced cell death in the
presence of CHX was characteristic of apoptosis (Fig. 1B). The Xiap
protein level, as determined by Western blotting,
was significantly increased by TNF (P < 0.01; Fig. 1C).
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-induced apoptosis-induced
apoptosis, granulosa cells were infected with adenoviral LacZ or
full-length Xiap antisense cDNA (MOI = 40). The Xiap protein level
was increased markedly (P < 0.05) by TNF alone, but
was significantly attenuated by adenoviral Xiap antisense infection
(P < 0.05; Fig. 2A).
Down-regulation of Xiap expression induced granulosa cell apoptosis,
which was further enhanced by the presence of TNF (P
< 0.01; Fig. 2B).
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B activation and translocation by NAC and SN50
potentiated TNF-induced apoptosisB activation is involved in
TNF-induced Xiap expression, we examined the temporal changes in
granulosa cell phosphorylated and total IB protein levels and
nuclear NFB binding ability after TNF stimulation. Addition of
TNF (20 ng/ml) to granulosa cell cultures resulted in an increased
phosphorylated IB level, which reached a maximum (5 min),
subsequently dropped to the pretreatment level (15–30 min), and then
gradually increased thereafter (60–120 min). The total IB level
remained constant until 5 min after TNF challenge, after which it
decreased significantly and returned to pretreatment levels at 60 min.
Nuclear NFB binding ability, as measured by EMSA, was markedly
increased after TNF challenge, reaching a maximum at 15 min, and
decreased gradually thereafter (Fig. 3A).
The increase in NFB binding capacity was specific, as it was
completely eliminated by the addition of a 50-fold excess of unlabeled
NFB probes (Fig. 3B).
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B level by TNF (20 ng/ml) and inhibited TNF-induced
NFB translocation and activation in a concentration-dependent manner
(Fig. 3B
). Inhibition of TNFinduced granulosa cell NFB
activation by NAC enhanced apoptosis induced by TNF
(P < 0.01; Fig. 3C). Similarly, addition of SN50 to
granulosa cell cultures 15 min before TNF challenge markedly
attenuated the NFB activation, as evident by suppressed nuclear
NFB binding activity in a concentration-dependent manner. However,
the same concentrations (100 and 200 µg/ml) of the inactive peptide
SM50 were ineffective (Fig. 4A). The
TNF-induced Xiap protein level was attenuated by SN50
(P < 0.01; Fig. 4B).
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-induced apoptosis in the
presence of the either SN50 or NAC (20 ng/ml; 6 h later) exhibited extensive apoptosis
(P < 0.01). In contrast, overexpression of Xiap with
adenoviral Xiap sense cDNA (MOI = 5; 24 h) before treatment
with TNF plus SN50 or NAC resulted in a significant reduction in the
number of apoptotic cells (P < 0.01, Fig. 5A; P < 0.05, Fig. 5B).
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Discussion |
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is an intraovarian regulator of follicular development and
atresia. However, its role in the induction of apoptosis in ovarian
cells remains controversial. TNF has been shown to inhibit ovarian
cell viability and proliferation (14) and to attenuate the
antiapoptotic effect of FSH on granulosa cell of cultured rat early
antral follicles (15). Although TNF promoted
Fas-mediated killing in cultured murine granulosa cells, it alone
failed to induce apoptosis (30). We have demonstrated in
the present study that TNF alone is unable to induce apoptosis in
cultured rat granulosa cells. The activity of TNF in different cell
types is predominantly determined by a balance between
apoptosis-inducing and cell survival factors (36). The
binding of TNF to its receptor activates procaspase-8 and possibly
other initiator caspases (37). Caspase-8 cleaves and
activates caspase-3 and other downstream caspases, such as caspase-7,
an ultimate effector of apoptosis. The inability of TNF to induce
apoptosis in granulosa cells might be due to the induction of Xiap
expression, which is able to directly inhibit procaspase-3, -7, and -9
cleavages, well established cell death processes by caspase activation
(38, 39, 40, 41, 42). Indeed, results from the current studies have
shown that treatment of granulosa cells with TNF markedly enhanced
the Xiap level. Blockade of TNF-induced Xiap expression by CHX or
Xiap antisense facilitated the induction of apoptosis by the cytokine.
Alternatively, although the relative expression of the two TNF
receptor subtypes (i.e. TNFR1 and TNFR2) during follicular
development has not been investigated and may account for the above
differences in the response of the cells to the cytokine, this latter
contention remains to be demonstrated. On the contrary, studies with
human keratinocytes have suggested that its sensitivity to TNF was
not simply correlated with the number of TNF receptors
(36). In addition, the protective effect of TGF on
TNF-induced apoptosis in the presence of CHX was not related to
reduced expression of the 55-kDa TNFR, although the relative abundance
of the surface receptor was inversely proportional to cell density
(36).
The role and regulation of NFB signaling in the ovary by TNF have
not been investigated. In the present study we demonstrated that
addition of TNF to granulosa cell cultures resulted in a rapid
increase in the phosphorylated IB protein level, activation of
NFB, and up-regulation of Xiap expression. It has been demonstrated
that NFB activation and gene expression induced by TNF are
mediated by reactive oxygen species (43) and that these
events can be inhibited by the intracellular radical scavenger NAC
(44). In addition, SN50 is a cell-permeant peptide
containing the nuclear localization sequence of the p50 subunit of
NFB and is linked to part of the signal peptide of Kaposi fibroblast
growth factor. It binds and retains the NFB complex at the nuclear
membrane, thus reducing its translocation into the nucleus
(45). If TNF-regulated Xiap expression is mediated by
NFB activation, it is expected that inhibition of TNF-induced
NFB activation should block up-regulation of Xiap expression by
TNF. In this study pretreatment of granulosa cells with the nuclear
localization peptide SN50 attenuated both NFB activation and the
increase in Xiap protein level induced by TNF, suggesting that
TNF-induced Xiap expression in granulosa cells is mediated by the
IB-NFB signal pathway. These findings are consistent with the
concept that NFB is normally sequestered in the cytoplasm as a
complex with IB, which masks the nuclear translocation signal of
NFB (46). TNF receptor binding, particularly that of
TNFR1, results in the recruitment of a number of intracellular proteins
[e.g. TNFR1-associated death domain protein,
TNFR-associated factor 2, receptor interacting protein]
(47) to the receptor, the phosphorylation and release of
IB from the complex, and the translocation of NFB from the
cytoplasm to the nucleus for transcriptional activation. Our results
are in agreement with the observations that NFB mediates the action
of TNF in the regulation of Xiap expression in primary human
endothelial cells (27).
It is possible that Xiap may not be the only antiapoptotic gene
activated by NFB in granulosa cells and that other cell survival
factors may be involved in the action of the cytokine. We have recently
demonstrated that the flice-like inhibitory protein and Bcl-2 proteins
are present in both cultured rat granulosa cells and human ovarian
surface epithelial cancer cells and are up-regulated by TNF in a
NFB-mediated mechanism (Xiao, C. W., and B. K. Tsang,
unpublished data). In addition, bcl-2 gene expression in rat
primary hippocampal neurons is increased after TNF stimulation, and
NFB appears to be involved in the regulation of this response
(48). Although increasing evidence shows that the
activation of NFB is involved in cell activation and proliferation
(49, 50, 51, 52), several lines of evidence also indicate that
activation of NFB may be involved in the regulation of apoptosis
(53). NFB can up-regulate the expression of c-Myc and
p53 in neuronal cells, Fas in hepatocytes (54), and FasL
in T cells (55, 56) and is responsible for the apoptotic
response to various stimuli (54, 57). In the ovary,
Fas/FasL is believed to play an important role in follicular atresia,
and their appearance is consistent with the localization of apoptosis
and is well correlated with follicular atresia (58).
TNF has been shown to increase Fas expression in cultured murine
granulosa cells and to enhance the agonistic Fas antibody-induced cell
killing (30). The role of NFB in the regulation of
Fas/FasL system during follicular atresia remains to be determined.
The endocrine and intraovarian regulation of Xiap expression during
follicular development and atresia is poorly understood. Previous
results from our laboratory have shown that Xiap expression is closely
related to granulosa cell proliferation and apoptosis during follicular
development and atresia, respectively. It is highly expressed in
proliferating granulosa cells of eCG-primed healthy follicles and
down-regulated in apoptotic cells from atretic follicles after
gonadotropin withdrawal (5). Using a rat follicle culture
system coupled to an adenoviral gene-manipulating process, we have
recently demonstrated that granulosa cell apoptosis increased while the
Xiap level decreased when cultured in the absence of FSH and that
addition of gonadotropin to the follicle cultures was able to attenuate
these responses (Wang, Y., et al., unpublished data).
Whereas overexpression of Xiap by sense cDNA prevented the apoptosis
observed in the absence of FSH, infection of follicles with adenoviral
Xiap antisense down-regulated Xiap expression and suppressed
FSH-induced granulosa cell survival, suggesting that Xiap plays an
important role in the regulation of granulosa cell survival by
gonadotropin during follicular development (Wang, Y., et
al., unpublished data). In addition, the effect of gonadotropin on
follicular growth appears to be mediated through the synthesis and
action of TGF and may involve the regulation of granulosa cell Xiap
expression (Wang, Y., and B. K. Tsang, unpublished data). The
present demonstration of the up-regulation of granulosa cell Xiap by
TNF represents a new aspect of intraovarian regulation of Xiap
expression and its importance in granulosa cell fate determination.
In conclusion, our present studies have demonstrated that TNF is a
survival signal in rat granulosa cells in vitro, and that
Xiap plays an important regulatory role in granulosa cell apoptosis.
TNF alone is incapable of inducing apoptotic cell death. The
inability of the cell to undergo apoptosis in response to the cytokine
is due in part to the NFB-mediated induction of Xiap.
Received August 9, 2000.
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J.T. Bridgham and A.L. Johnson Alternatively Spliced Variants of Gallus gallus TNFRSF23 Are Expressed in the Ovary and Differentially Regulated by Cell Signaling Pathways Biol Reprod, April 1, 2004; 70(4): 972 - 979. [Abstract] [Full Text] [PDF]
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H. C. Dan, M. Sun, S. Kaneko, R. I. Feldman, S. V. Nicosia, H.-G. Wang, B. K. Tsang, and J. Q. Cheng Akt Phosphorylation and Stabilization of X-linked Inhibitor of Apoptosis Protein (XIAP) J. Biol. Chem., February 13, 2004; 279(7): 5405 - 5412. [Abstract] [Full Text] [PDF]
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