ELSEVIER
European Journal of Obstetrics & Gynecology
and Reproductive Biology 67 (1996) 85-102
oBM
GYNECI)U
Review article
Apoptosis: A programmed cell death involved in ovarian and uterine
physiology
D. Vinatier*, Ph. Dufour, D. Subtil
Hdpital Jeanne de Flandre, Chru de Lille, F 59037 Lille Cedex, France
Received 2 February 1996; accepted 14 April 1996
Abstract
Apoptosis is a form of programmed cell death which occurs through the activation of a cell-intrinsic suicide machinery. The biochemical machinery responsible for apoptosis is expressed in most, if not all, cells. Contrary to necrosis, an accidental form of cell
death, apoptosis does not induce inflammatory reaction noxious for the vicinity. Apoptosis is primarily a physiologic process
necessary to remove individual cells that are no longer needed or that function abnormally. Apoptosis plays a major role during
development, homeostasis. Many stimuli can trigger apoptotic cell death, but expression of genes can modulate the sensibility of
the cell. The aim of this review is to summarise current knowledge of the molecular mechanisms of apoptosis and its roles in human
endometrium and ovary physiology.
Keywords: Apoptosis; Homeostasis; Ovary; Uterus
1. Introduction
The numerous intercellular interconnections that
characterise advanced forms of life would not be working without mechanisms able to remove individual cells
that are no longer needed or that function abnormally.
The main characteristic of apoptosis is to eliminate cells
without inducing local inflammatory response, susceptible to damage adjacent cells. During apoptosis, the
undesirable cells are prepared before detaching their
neighbouring cells and being phagocytized by macrophages. Ingestion of cellular components by macrophages does not induce the leakage of noxious
proteolytic enzymes or reactive oxygen metabolites.
Apoptosis is a physiological cell death which interferes during life as proliferation and differentiation
do. Apoptosis takes place during embryo genesis as a
force in sculpting the developing organism, in the course
of normal tissue turnover maintaining precise cell
numbers and after withdrawal of a t r o p h i c hormone
from its target tissue [1]. Apoptosis serves as a defence
* Corresponding author.
mechanism to remove unwanted and potential
dangerous cells, such as self-reactive lymphocytes, cells
that have been infected by virus and tumour cells. In addition to the beneficial effects, the inappropriate activation of apoptosis may contribute to the pathogenesis of
many diseases such as cancer, neurodegenerative disorders, autoimmune diseases, acquired immunodeficiency syndrome and resistance to chemotherapy (Table 1).
2. Definition of apoptosis
Apoptosis is considered to be operationally, morphologically and biochemically distinct from necrotic
cell death (Table 2) [2,3].
Table l
Diseases associated with dysregulationof apoptosis
Decreased apoptosis
Increased apoptosis
Cancer
Neurodegenerative disorders
Auto immune diseases
Viral infections
Chemotoxic resistances
Lymphoproliferative diseases
AIDS
Myelodysplastic syndromes
Ischemic injury
Toxic induced diseases
0301-2115/96/$15.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved
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D. Vinatieret al./European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 85-102
Table 2
Differentaspects betweenapoptosis and necrosis
Necrosis
Apoptosis
Irregular clumpingof chromatine.
Fragments are ill-definedand dispersed into the nuclear
Disruption of nucleus
Well regular definedcondensationof chromatin. Condensationsare
marginated against nuclearenvelope
Fragmentationinto a double-layeredenvelope
Swellingof the cell
Cytoplasmiccondensation
Organelles remain well preserved
Convolution of nuclear and cell outlines
Phagocytosis
No associated inflammation
Swellingof the cell
Swellingof organdies
Focal disruption of cell membranes
No phagocytosis
Local inflammation
2.1. Morphologic and biochemical characteristic o f apoptosis
The chromatin rapidly forms dense and crescentshaped aggregates ,lining the nuclear membrane.
Simultaneously cytoplasm condenses. Desmosomes are
destroyed, while intercellular spaces enlarge. Endoplasmic reticulum, mitochondrias and membrane remain intact and metabolically active for many hours [4].
Progression of condensation is accompanied by ruffle
and convolution of the nuclear and plasma membrane.
The nucleus is then broken up into discrete fragments
that are surrounded by a double-layered envelope. Cytoplasmic membrane buds to produce membrane-bounded
apoptotic bodies. The size and the content of these
apoptotic bodies vary considerably. Some include nuclear fragments, while others are empty. The cytoplasmic organelles of newly formed apoptotic bodies remain
preserved. Apoptotic bodies are quickly ingested by the
nearby cells where they are degraded [5]. There is no
spillage of pro inflammatory cell contents, and the
Fig. 1. (1) left panel: Chromatineformsdense and crescent-shapeaggregates lining the nuclear membrane. (2) right panel: conventional
electron microscopyshows convolutionsof plasma membrane(provided very kindlyby Dr. ldziorek from Institut Pasteur, Lille).
phagocytes that ingest an apoptotic cell do not become
activated as they would if they ate an opsonized particle
[2]. Once initiated apoptosis is accomplished very quickly, with only a few minutes elapsing between onset of the
process and the formation of apoptotic bodies which
completely digested within hours (Fig. 1).
2.2. Molecular mechanisms
2.2.1. Nuclear metabolic changes during apoptosis
The most characteristic feature of apoptosis, the condensation of nuclear heterochromatin, is associated with
a unique change in the nuclear DNA. The nuclear DNA
is cleaved between nucleosomes that produces fragments
in multiples of approximately 180 bp [6]. This phenomenon is most often analysed by agarose gel electrophoresis which measures DNA fragmentation in
nuclear extracts showing the typical 'DNA ladder' configuration (Fig. 2) [6] contrasting with the migration of
the randomised breakdown observed during necrosis.
The analysis of DNA degradation provides a useful tool
to detect apoptosis, because internucleosomal fragmentation is almost always detected when the morphological
changes of apoptosis are recognised [7-11]. But the internucleosomal DNA fragmentation is not universal,
sometimes it does not occur during apoptosis [12-14].
Formation of high-molecular-weight DNA fragments
precedes the oligonucleosomal DNA fragmentation and
may signal the irreversible commitment to apoptotic cell
death [15,16].
Biochemical studies have provided evidence that a
Ca2+/Mg2+-dependent endonuclease is involved in nuclear fragmentation [6,17-19]. The presence of a
Ca2+/Mg2+-dependent endonuclease capable
of
generating characteristic apoptotic chromatin cleavage
has been demonstrated constitutively within nuclei from
a variety of cell types [20-23]. Involvement of Ca 2+ and
Mg 2 is suspected because numerous inducing apoptosis
signals elevate intracellular Ca 2+ [24-27]. Calcium
ionophores induce lymphocytes T apoptosis [28-30].
Ca 2+ removal prevents high molecular weight and inter-
D. Vinatier et al./ European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 85-102
87
Agents known to modify chromatin structure (i.e.
polyamines) can prevent DNA fragmentation and apoptosis of thymocytes exposed to glucocorticoids and
Ca 2+ ionophores [39]. As intracellular depletion of
polyamines results in alteration of chromatin structure
in intact cell [40], it is probable that polyamines may
play a role in controlling endonuclease activity by modifying the degree of chromatin accessibility. In vitro
depletion of intracellular polyamines directly results in
alteration of DNA supercoiling and increased sensibility
of nuclear DNA to digestion by endogenous or exogenous DNAases [40]. Thymocytes incubated with an
inhibitor of polyamine synthesis are more prone to apoptosis induced by glucocorticoids [41].
Endonuclease-mediated
internucleosomal
DNA
cleavage will take place only when the internucleosome
regions are accessible by a decondensation or a local
reduction in histone-DNA interaction.
If chromatin structure is a key determinant in DNA
fragmentation during apoptosis, all the factors susceptible to modify this structure are prone to modulate apoptosis. For example, some cytokines and protein kinase
C modulate apoptosis after affecting chromatin structure. Cytokines can act by modulating the intracellular
concentration or by inducing phosporylation of histone
proteins. A serine protease activated just before endonuclease could facilitate apoptosis [42,43] in hydrolysing
proteins located between nucleosomes [44].
2.2.2. Cytoplasmic modifications
Fig. 2. Agarose gel electrophoresis of the nuclear DNA showing the
typical 'NA lader' configuration (due to the courtesy of Dr. ldziorek
from lnstitut Pasteur, Lille).
nucleosomal DNA fragmentation in thymocytes exposed to glucocorticoids or topoisomerase II inhibitor [26].
Specific Ca 2÷ channel blockers abrogate apoptosis in
the regressing
prostate following testosterone
withdrawal [31] and in pancreatic beta islets treated with
serum from diabetes type I patients [32]. However in
some systems, Ca 2÷ antagonists have no effect [33-35],
and sometimes elevation of Ca 2+ blocks apoptosis [36].
Ca2÷independent endonuclease (ADNase I) involved in
nuclear DNA degradation have been identified during
apoptosis [221.
Intracellular elevation of Ca 2÷ is unlikely to be the
second messenger of apoptosis triggering, since
numerous growth factors and hormones induce elevation of intracellular Ca 2÷ without inducing apoptosis
[37].
If Ca2÷/Mg2÷-dependent endonuclease would require
Ca 2÷ for activation, an alternate possibility is that Ca 2÷
could play a role in modifying chromatin conformation,
making chromatin regions accessible to enzymes such as
DNAase I or other endonucleases [38].
The cytoplasmic condensation is associated with an
increased density and a 30% reduction of cellular
volume [45]. The mechanisms involved in these process
are still unknown. The cytoskeletal elements are major
participants of apoptotic body genesis. Calpain, a protease which disrupts cytoskeleton, induces apoptosis. In
cells destined to undergo apoptotosis, B-tubulin
messenger RNA increases before the development of
morphologic changes and the occurrence of DNA
cleavage. Latter increased amounts of/~-tubulin appear
in the cytoplasm. Agents, that interfere with actin
polymerisation, prevent the cellular budding that leads
to the formation of apoptotic bodies without affecting
fragmentation of the nucleus and DNA cleavage [461.
A Ca2÷-dependant cytoplasmic transglutaminase is
synthesised [47,48] and activated [49,50] during apoptosis. The highest concentrations of the enzyme are present in the apoptotic bodies. This enzyme is involved in
the cross linking of intracellular proteins resulting in a
rigid framework within apoptotic bodies, which aids in
maintaining their integrity and thus preventing leakage
of their contents.
The nucleus is not the sole target of apoptosis nor
does it participate in an obligatory fashion in the regulation of apoptosis. Using cell-free systems in which
isolate nuclei are combined with cytoplasmic com-
88
D. Vinatier et al./ European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 85-102
ponents, it has been discovered that certain cytoplasmic
proteases are capable of activating nuclear destruction
[51]. A cystein protease (ICE, interleukin-1-/~converting enzyme) may function in mammalian cell
death [52]. The transfection of the ICE gene into rat
cells in culture shows that production of ICE protein
killed the cells. Mutations of this transfected gene abolish its apoptotic properties [53]. Inhibition of ICE activity by protease inhibitors, as well as by transient
expression of the pox virus-derived serpin inhibitor Crm
A or an antisense suppressed, triggered cell death
[54-56]. ICE has a rather unusual substrate specificity,
cleaving at Asp-X bonds (where X is any aminoacid).
This specificity is shared with only one known protease,
granzyme B, a serine protease. Granzyme B induces
apoptotosis of target cell of cytotoxic T cells [57]. Granzyme B and ICE activities are blocked by the same
agents. The ICE protease family has recently expanded
with the discovery of three homologous cystein proteases: (i) l-Ich-I with two molecules, Ich-1 short inhibitor of apoptosis and Ich-1 long inductor of apoptosis
[53]. (ii) 2-CPP32 (cysteine protease-P32) [58], which
gives birth after hydrolysis to apopain, the apoptosis inducing molecule [59]. (iii) 3-Tx protein [60]. Two important proteins involved in cellular homeostasis
poly(ADPribose)polymerase and U1 small nuclear
ribonucleoprotein have been identified as substrates of
the ICE proteases during apoptosis [61-63].
Crude cytoplasmic extracts from Xenopus oocytes induce nuclear apoptosis provided they contain
mitochondria-enriched fractions [64]. Sequential
dysregulation of mitochondrial function that precedes
cell shrinkage and nuclear fragmentation has been
reported [65]. That alterations of mitochondrial
physiology reported by some [66] as a constant feature
of very different systems of apoptosis induction is still
disputed by others who reported apoptosis induction
after mitochondrion depletion [671.
2.2.3. Cell membrane alterations
Conventional electron microscopy, supported by
freeze fracture analysis, showed a constant migration of
nuclear pores toward the diffuse chromatin areas. In
contrast, dense chromatin areas appear pore-free. Diffuse chromatin represents the DNA arrangement corresponding to active replication and transcription, while
condensed chromatin is a temporarily quiescent form.
Exclusive pore clustering around the remaining diffuse
chromatin areas might be due to the localization of residual nuclear activity in these areas [68].
A critical event during program cell death appears to
be the acquisition of plasma membrane changes that
allows phagocytes to recognise and engulf these cells
and apoptotic bodies before they rupture. Several alterations of the cell membranes have been reported depending on the origins of the apoptotic cells and on the
phagocytes [69]. Some cells, when apoptotic, bind asyet-uncharacterized extracellular factors that are engaged by the vitronectin receptors on certain macrophages
[6,70]. Transfection of macrophage adhesion molecule
CD36 gene into epithelial cells confers them capacity for
phagocytosis of cells undergoing apoptosis [71]. Others
cells expose phosphatidylserine on the external leaflet of
the plasma membrane lipid bilayer, where it is recognised by a receptor possessed by macrophages [72]. Macrophages elicited from the peritoneal cavities of mice
specifically recognised apoptotic cells in a manner that
was inhibited by liposomes containing phosphatidylserine, but not by liposomes containing other
aminophospholipids [72]. Under conditions in which
the morphological features of apoptosis were prevented,
the appearance of phospatidyl serine on the external
leaflet of the plasma membrane was similarly prevented.
The inside-outside phosphatidylserine flip out may be
an early and widespread event during apoptosis [73].
Protease calpain activated by elevation of cytoplasmic
Ca2+activation may induce downregulation of
translocase and activation of scramblase, responsible for
phosphatidyl serine flip out [741.
Many apoptotic cells have a reduced capacity for adhesion due to down regulation of the levels of surface expression
of
receptors/ligand
which
control
adhesive-molecule adhesion. The altered adhesive potential of the apoptotic cell may serve to limit release of
its noxious contents and reduce inappropriate tissue injury [751.
3. Incidence of apoptosis in normal tissues
Apoptosis accounts for the deletion of cells that occurs in normal tissues, and it is observed in certain
pathologic conditions [2,3,76,77].
Physiologic cell death is a prominent feature in tissue
development where it serves as part of the process of
organ formation [78] (in this context it is called morphogenetic death) [79]. In embryogenesis, apoptotic cell
death functions to eliminate unnecessary cells during tke
development process [80,81].
Germ cell death is conspicuous during spermatogenesis and plays a pivotal role in sperm output
[82]. In early development, many blastomeres die by
apoptosis [3,6]. Apoptosis occurs during organogenesis
of heart [83], duodenum, pancreas [84] and urogenital
tract [85]. During limb formation, apoptosis plays a significant role in the separation of digits as well as the formation of joint cavities [86,87].
Many of the neurons which migrate to the cortex die
at an early stage of development. If the axon of the cell
does not make contact with the dentrites of the cell in
its target area it will die [88,89]. The massive neuron
death is thought to reflect the failure of these neurons to
obtain adequate amounts of specific neurotrophic fac-
D. Vinatier et al./ European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 85-102
tors that are produced by the target cells and that are required for neurons to survive [90]. Examples are given
of the effect of sensory deprivation on the survival of
neurons. Early sensory stimulation plays a key role in
the shaping and function of the developing nervous system. Olfactory deprivation by unilateral naris occlusion
of rat pups causes a dramatic increase in apoptotic cell
death in the cell layers of the deprived bulb [91]. The
neuron death can be a factor in the fine tuning of neural
circuits and, therefore, in an improvement in learning
and the development of skills [92,93]. During ontogeny
of the immune system, the self reactive lymphocytes are
normally deleted by apoptosis at an immature stage of
their development [94].
In adult, steady-state conditions prevail in most organ
systems: for each that divides, another must die or be
shed to the exterior. In general, the lifespan of cells is inversely proportional to production rate. Apoptosis occurs continually in slowly-proliferating cell populations,
such as liver [95,96], prostate and adrenal cortex [5] and
in rapidly dividing tissues, such as epithelium of the
stomach [97] and spermatogonies [98].
It remains a mystery how the balance between cell
death and cell proliferation is maintained. It seems likely
that both cell survival and proliferation are controlled
so that they occur only if stimulated by signals from
other cells. It has been postulated that most cells in
higher animals may require continuous trophic stimulation to survive. Raft has postulated that an increase in
cell numbers in a particular location might lead to greater cellular competition for the trophic factors that stimulate mitosis and inhibit apoptosis and that, in turn,
might temporarily tip the balance between the two processes, leading to restoration of cell population of the
cell population to its former level [99].
89
Apoptosis might be involved in a number of involutional processes occurring in normal life such as the involution of the breast glands after suspension of
lactation [1001, the ovarian follicular atresia [101]. Apoptosis may mediate the decrease in cellularity during
wound healing [102].
4. Regulation: apoptosis or survival
The fate of a cell relies upon balance between several
intrinsic and extrinsic influences. In general, anything
that produces necrosis by direct cell destruction can induce apoptosis if the cell initially survives [103]. Apoptosis represents a co-ordinated cellular response to
noxious stimuli that are not immediately lethal. The list
of signals either stimulating (Table 3) or inhibiting
(Table 4) grows daily.
4.1. Physical insults
Ionising radiations [104-106], heat shock [107] and
UV radiation [108,109] enhance apoptosis. Many drugs
as diverse as topoisomerase inhibitors, alkylating agents
and antimetabolites [110,111] have been shown to induce extensive apoptosis in rapidly-proliferating normal
cell populations, lymphoid tissues and tumours. The
enhanced apoptosis is responsible for many of the adverse effects of chemotherapy and for tumour
regression.
4.2. Growth factors and cytokines
It has been postulated that most cells may require
continuous trophic stimulation to survive [1121. Privation of these factors such as interleukin-2 (II-2)
Table 3
Inducers of apoptosis
Physiologic activators
Chemicals
Biological factors
Toxins
Therapeutic agents
TNF family
Fas ligand
TNF
TGF-B
Calmodulin
Calcium
Trophic factor withdrawal
Glucose
Growth factors
IL-2,-3,-10,-13
TGF/~
Neurotrophic factors
Hormones
IL-IB converting enzyme
Tissue transgiutaminase
Loss of matrix attachment
Free radicals
Glutamate
Azide
Hydrogen peroxyde
Viral infection
HIV
Baculovirus
Cytotoxic T cells
Cytokines
TNF-a
TGF-0
Hyperthermia
Extented culture in vitro
Heat shock protein
Ethanol
Aflatoxin
Retinoic acid
0-amyloid peptide
Glucocorticoid
Chemotherapeutic drugs:
cisplatin
doxorubicin
bleomycine
cytosine
arabinoside
methotrexate
vincristine
nitrogen mustard
7 radiation
UV radiation
Ca 2+ ionophores
Digoxyn
RU 486
Prostaglandin E2
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D. Vinatier et al./European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 85-102
Table 4
Inhibitors of apoptosis
Physiologicinhibitors
Viral genes
Pharmacologicalagents
Growth factors
Cytokines
Extracellular matrix
Papillomavirus
Adenovirus
Baculovirus
Cowpox virus
Pox virus
Herpes virus
Epstein-Barr virus
Calpain inhibitors
Cysteineprotease inhibitors
Trolox
Phenobarbital
a-hexachlorocyclohexane
[113,114], IL-3 [115], II-6 [116,117], 11-13 [118], and colony stimulating factor (CSF-1) [118] induce apoptosis in
several cell populations.
In certain cells, the binding of TNF-ct to one of its
receptors (TNFr-I or TNFr-II) induces apoptosis
[119-126]. TNF-ct-induced apoptosis of hepatocytes is
greatly enhanced by interferon 7 [127]. TNF-c~ may activate some proteases involved in apoptosis [128]. TNFot is a member of TNF superfamily which comprises 4
members able to trigger apoptosis (TNF-ct, LT-ot, FASL and the recently described TRAIL). Although these
proteins, for the most part, exist as trimeric or
multimeric membrane-bound proteins which function to
induce receptor aggregation, there are a few members,
such as TNF-ot and FAS-L, which are functional in a
soluble form. These proteins exert their effects through
receptor-ligand interactions which induce downstream
signal transduction events. Their receptors (belonging to
the TNF receptor superfamily) are characterized by a
'death domain' in their cytoplasmic tail [129].
IL-4 [130] and transforming growth factor ~ induce
cell death of several cell populations [131-137].
IL-I has opposite effects depending on the target. It
inhibits glucocorticoid and T-cell receptor-induced
death of immature lymphocytes [27] and confers protection to mice irradiated with lethal doses of ionising radiation [138]. I1-1 inhibits apoptosis of monocytes in
culture [124]. IL-1 may be a survival factor for neurons
[139]. Inversely, IL-1 induces apoptose of many cell
populations [140-142].
5. Gene regulation of apoptosis
Apoptosis in an active form of cell death dependent
upon the internal machinery of the cell. In the earliest
examples of apoptosis to be studied, the cell needed to
make new mRNA and protein to die. Prevention of protein and mRNA synthesis by drugs such as actinomycin
D or cycloheximidine also prevented death [99,147]. The
concept of 'cellular suicide' derived from these examples. It appears that in these cases the cell's death is
not inevitable, and so when it is signalled, the cell needs
to promote at least some of the suicidal machinery.
These observations have inspired many studies devised
to identify and clone potential 'death genes'.
By contrast, the same inhibitors of mRNA and protein synthesis do not affect [148,149] or even stimulate
[150-152] apoptosis in others cell types. The nucleus is
not required for a cell to be able to undergo apoptosis
induced by staurosporine and by privation of survival
factors [51].
This suggests not only that many cells have the programme, but also that the protein components of the
programme are already expressed and are maintained in
association with inhibitors. Blockage of inhibitor synthesis induces apoptosis.
Once the inducing signals have been received, the cell
expresses genes either promoting or inhibiting the cell
death machinery. Expression of these regulator genes
may be regulated by external factors such as cytokines
[153] (Table 5).
4.3. Hormonal regulation
Both atrophy of endocrine-dependant organs after
hormonal withdrawal and the menstrual cycledependant changes in occurrence of apoptosis in human
tissues suggest that this process is subject to regulation
by steroid hormones. Increased levels of glucocorticoids
induce apoptosis in thymocytes [3]. Androgen ablation
induces apoptosis in prostatic glandular epithelial cells
[143]. Oestrogen withdrawal induces apoptosis in the
endometrium and in the steroid -sensitive cells
[144,145]. Progesterone suppressed and its antagonist
RU 486 induced apoptosis [146].
Table 5
Genes involvedin regulationof apoptosis
Intracellular inducers
Intracellular suppressors
p53
c-myc
bax
bcl-x short
c-fos
bad
bcl2
bcl-x long
D Vinatier et al./European Journal of Obstetrics & Gynecolog) and Reproductive Biology 67 (1996) 85-102
5.1. Intracellular inducer of apoptosis
5.1.1. c-myc
The nuclear proto-oncogene c-myc has been implicated in the control of cell proliferation and differentiation, c-myc protein level is higher in proliferating
cells than in quiescent cells, indicating that expression of
c-myc is necessary for cell proliferation. Downregulation of c-myc triggers growth arrest and cell differentiation. Paradoxically, it has been shown that c-myc plays
a role for apoptosis [154]. c-myc is overexpressed in the
rat ventral prostate gland after castration which induces
apoptosis. The peak level of transcription is reached at
the stage of involution when apoptosis is at its maximum [155]. Persuasive data from transfection [156] and
antisense oligonucleotide experiments [157] clearly
demonstrate that c-myc can trigger apoptosis in cells
deprived of survival factors [1581 or exposed to heat
shock [158]. Requirement of c-myc transcription is not
universal since the antisense oligonucleotides have no
effect on the induction of apoptosis in the T-cell hybridomas by glucocorticoids, while they inhibit the
activation-induced apoptotosis in the same hybridomas
[157,160]. Thus, c-myc product can induce both cell proliferation and apoptosis. Cellular decision between these
opposite responses is determined by other regulatory
genes that may provide a second signal to inhibit apoptosis and allow c-myc to drive cells into proliferation
[159,161]. Gene transfer experiments have demonstrated
that overexpression of c-myc can result in mitosis or
apoptosis, depending on the availability of others
growth factors [156,158,159,162]. In the presence of
such factors, c-myc acts as a classic proto-oncogene,
stimulating mitosis, and in their absence it initiates apoptosis [11. The mechanism by which c-myc influences
apoptosis is not known. Several experiments have
demonstrated a cooperative interaction between c-myc
and others genes (bcl-2, p53) in making life or death
decisions for the cells [ 159,163,164].
5.1.2. p53
Abnormalities of p53 tumour suppressor gene constitute some of the most frequently encountered genetic
defects in human cancer [165]. Transfection of the wildtype p53 gene into cells usually lacking p53 activity has
identified a number of p53-mediated functions
[165,166]. They include growth arrest, which occurs primarily in the GI phase of the cell cycle, and cellular differentiation [167]. Involvement of p53 in apoptosis has
been suggested since it has been observed that transfection of p53 induces extensive apoptosis in two p53negative cell lines [168,1691. Intestinal epithelial cells require normal p53 function for induction of apoptosis
after v-irradiation. The apoptotic response is p53-dose
dependant [170].
Thep53 monitors the integrity of the genome. If DNA
is damaged, the p53 accumulates and switches off repli-
91
cation to allow time for repair mechanisms. When the
repair of DNA fails, p53 may trigger deletion of the cell
by apoptosis [171-173]. Expression of p53 is mainly the
result of DNA damage [174] but not exclusively [175].
p53 is a 393-amino acid nuclear protein that binds
specifically to DNA and can act as a positive transcription factor. The WAF-1/Cipl is an important p53 target.
The p21 wAr/clvt, WAF-1/Cipl gene product associates
with and inhibits cyclin-Cdk complex kinase and
thereby blocks the transition from G1 to S in the cell cycle [176,177]. Overexpression of p21 wAr/ctet induces
growth arrest and apoptosis in human breast carcinoma
cell lines [178]. The mechanisms of WAF-1/Cipl regulation involve p53-dependent and p53-independent
signalling pathways [179]. The DNA-damaging agent
etoposide induced p53 accumulation only in cells harbouring wild-type p53 yet it induced WAF1/Cipl expression in cells carrying wild-type or mutant p53 [180].
p53-independent apoptotic pathways have been
described in the colon [181]. Apoptosis can occur in the
absence expression of p53 after treatment of thymocytes
with glucocorticoids or calcium ionophores [182,183].
Thymic lymphoma cell from p53-/-mice underwent apoptosis following irradiations [184]. Etoposide and
bleomycine induce p53-independent apoptosis in fibroblasts [185]. Some cell lines undergo p53-dependent and
p53-independent apoptosis, depending upon the initiating stimulus that triggers DNA damage [186].
5.1..3. Others genes
Several others genes have been implicated in induction of apoptosis, nurr 77 is transcripted in the pathway
of apoptosis induced by TCR triggering in thymocytes
[1871. c-fos and jun are overexpressed in thymocytes
apoptosis induced either by interleukin privation or by
glucocorticoid treatment [188,189]. An antisense construct of these gene inhibits apoptosis [190].
Fas ligand (FasL), a cell surface molecule belonging
to the tumour necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells.
Various cells express Fas, whereas FasL is expressed
predominantly in activated T cells [191], but not exclusively [1921.
5.2. Intracellular suppressors of apoptosis
bcl-2 has been discovered as a gene translocated from
its normal position on chromosome 18 to chromosome
14 [193]. All hematopoietic and lymphoid cells, many
epithelial cells, and neurons contains bel-2 protein,
found mainly in the mitochondrial membranes, nucleus
and endoplasmic reticulum [194,195]. bcl-2 has been
reported to prolong the survival of cells Transfection of
bcl-2 into interleukin-3-dependent myeloid cell lines
promoted survival of these cells after privation of
interleukin-3, but did not stimulate proliferation [196].
bcl-2 specifically inhibits apoptosis [194]. Overexpres-
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D. Vinatieret al. /European Journal of Obstetrics & Gynecologyand Reproductive Biology 67 (1996) 85-102
sion of bcl-2 can reverse the fate of cells undergoing apoptosis both in vivo and in vitro in many cell systems in
response to a variety of stimuli, such as growth factor
privation [198,199], radiation, treatment with corticoids
[200], in viral infections [201,202], and by chemotherapeutic drugs [203]. Overexpression of bcl-2 protects neurons from ischemia induced apoptosis [204]. Transgenic
mice bearing bcl-2 [205,206] and induction of bcl-2 into
hematopoietic cells promote cell survival [196]. Inhibition of bcl-2 with antisense oligonucleotides induces
apoptosis of acute myeloid leukaemia [207]. Since these
signals are diverse, it is likely that bcl-2 blocks a final
pathway that is common in apoptosis of diverse
aetiologies.
However, in vivo and in vitro bcl-2 cannot block all
types of apoptosis [208]. Bcl-2 prevents apoptosis in
hematopoietic cell lines dependant on IL-3, or IL-4, but
it fails to prevent apoptosis in other cell lines after IL-2,
or IL-6 deprivation [199]. Overexpression of bcl-2 fails
to prevent antigen-mediated receptor in some B cell lines
[209]. Bcl-2 transfection can prevent radiation- and calcium ionophore-induced apoptosis in thymocytes but
does not prevent negative selection [206]. bcl-2 fails to
block apoptosis induced by cytotoxic T cells [208].
bcl-2 is the most representative member of a family of
genes that control cell homeostasis processes. Some
members of the bcl-2 family (Bcl-2, Bcl-x long) inhibit
apoptosis; whereas some others (Bax, Bcl-x short, bad)
induce it. Apparently the mere presence of Bcl-2 is not
enough to save cells from mortality. Bcl-2 must first win
a sort of hand-to-hand competition with Bax, its deathpromoting twin [210].
Bcl-2-Bax pair constitutes a 'pre-set rheostat' within
cell', with the ratio of Bcl-2 to Bax determining whether
a cell receiving a death order accepts it or ignores it. If
the Bcl-2 protein is in excess in a cell, it binds up all the
bax, and the rest of the Bcl-2 molecules pair with each
other. Under these conditions the cell survives. On the
other hand, if bax predominates, it grabs all the Bcl-2,
and forms Bax-Bax pairs. In that case the result is death
[211]. Bad, a heterodimeric partner for bcl-x long
displaces bax and promotes cell death [212].
Similarly, bcl-x, another member of the bcl-2 family,
encodes two functionally-different proteins, Bcl-x long
and Bcl-x short through differential splicing [213]. These
two forms of the Bcl-x protein may make up a competing pair like Bcl-2 and Bax. Excess of Bcl-x short induces cell death [214]. This expression of bcl-x could
account for several forms of apoptotic cell death
previously proposed to occur by intracellular mechanism that neither bypass or are regulated independently
of bcl-2 [200].
The genes involved in mitosis and apoptosis often interact. Bcl-2 protect from apoptosis induced by c-myc
[152,159,162,1641, freeing totally this gene to induce
proliferation [206]. Fas-mediated apoptosis is inhibited
by bcl-2 [215]. The oncogenic Ras protein upregulates
bcl-2expression [216]. The p53-dependent pathway of
apoptosis is inhibited by bcl-2 [217]. p53 inhibits bcl-2
transcription and stimulates bax [218].
bcl-2 exhibits two main biochemical properties: it acts
in an antioxidant metabolic pathway aimed at
eliminating oxygen free radicals that induce lesion in
DNA, lipids and proteins [219,220]; it modulates intracellular Ca++ fluxes inhibiting C a 2 + - dependent endonuclease activity. Precisely how bcl-2 regulates
apoptosis is still debated since it is able to protect from
apoptosis cells that lack of a nucleus or mitochondrial
respiration [51 ].
6. Apoptosis and uterus
The intensive proliferation in human endometrial epithelium observed during the proliferative phase of the
menstrual cycle ceases on the third day after ovulation.
In contrast to the cessation of proliferation in epithelial
cells, the proliferation in the stroma increases in the secretory phase. Most of this proliferative activity is due
to lymphoid population within the stroma [221]. Proliferation is highest in the epithelium in the upper functionalis and lowest in the basalis. Macrophages and T
cells, the main constituent of stromal lymphoid cell population [222], are attracted locally by the high concentration of progesterone during the proliferative phase
[223]. Lymphoid cells with their ability to secrete
cytokines design a polarised microenvironment which
presides over the destinies of epithelial cells, either proliferation or apoptosis and necrosis. Shortly after the description of apoptosis [2], basophilic granules, noted in
human endometrium in 1933 [224] have been identified
as apoptotic bodies [225]. The number of these granules
becomes significant during the secretory, premenstrual
and menstrual phases. The true nature of these granules
has been confirmed by in-situ demonstration of
fragmented DNA in the involved cells [226,227]. Apoptotic cells are scarce during proliferative phase. Their
population increases progressively during secretory
phase, peaking in the menstrual phase. Apoptosis affects
mainly epithelial cells and, less extensively, endometrial
stroma. Proliferation and apoptosis appear in two opposite poles of the menstrual cycle. Zona basalis is
characterised by low proliferative activity and high rate
of apoptosis, while functionalis epithelium is marked by
high proliferative activity and low apoptosis [228].
Bcl-2 is expressed in all the components of endometrium but at different phase of menstrual cycle. Bcl-2 expression
is
concordant
geographically
and
chronologically with proliferation. It starts in the glandular epithelium at the bottom of functional layer and
gradually spreads to all the glands. This expression is
most intense in the basalis glands, gradually diminishing
D. Vinatier et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 85-102
in the mid and upper functionalis glands [228-230].
Bcl-2 expression peaks at the end of proliferative phase.
Three days after ovulation most epithelial cells, with the
exception of some residing in the basalis, become bcl-2
negative for the duration of the secretory phase.
Bcl-2-negative endometrial cells can become susceptible
to signals inducing apoptosis. Apoptosis appears in
endometrium simultaneously with disappearance of
bcl-2. Stroma and lymphoid cells which are little affected by apoptosis express bcl-2during the whole cycle.
Bcl-2 is absent in the endothelial cells and present only
in the smooth muscle cells surrounding the vessels in the
basalis. Persistent expression of bcl-2 in the epithelial
cells residing within the basalis may account for the specific privilege that these cells have to escape apoptosis,
allowing these cells to contribute to the repair of the
endometrium after menstruation.
bcl-2 expression may be regulated steroid hormones
[231]. The dynamics of bcl-2 expression and its location
run parallel to the variation and distribution of specific
receptors for oestradiol and progesterone in glandular
epithelial cells, stroma and luminal epithelium [230].
The distribution of bcl-2 in the vascular compartment
also corresponds to a precise regulation and function, as
bcl-2 was not expressed in myometrial vessels but was
expressed strongly in spiral arteries, where oestradiol
and progesterone receptors have been located.
Fas antigen is expressed in endometrial epithelium
and vaginal epithelia throughout the entire menstrual
cycle [192]. This expression progressively diminished
from the basalis toward the upper functionalis. Whether
Fas antigen and Fas ligand (FasL) participate in the
apoptosis of endometrium is still disputed [228]. Fas
ligand-induced apoptosis might be a mechanism of immune privilege protecting the embryo allograft from
damages [232].
Repeated injections of oestradioi to animals (mice,
rabbit and hamster) inhibit the cell death usually induced by ovariectomy [10,233]. Apoptosis occurs when
oestrogens are withdrawn [233].
Administration of progesterone to rabbits inhibits the
apoptosis induced by ovariectomy [137]. Administration of RU 486 in rabbits and rhesus monkeys treated
with oestrogens induces apoptosis, reaching to levels
comparable to those attainable in the ovariectomized
animals [234,235].
The numerous local variations noticed in the endometrium affecting proliferation, apoptosis and function
may be secondary to microenvironments carrying out by
cytokines. To illustrate this organisation, IFN-7activated T cells induce HLA-DR expression and endometrial epithelial cell proliferation. The maximum of
influences is located in zona basalis where the lymphoid
cells (macrophages and T cells) are located. TNF-a, a
major product of these cells, is expressed in human
endometrium and has suscited numerous studies. TNF-
93
o~ in a time- and dose-dependant fashion induces apoptosis of cultured endometrial cells [224].
The progressive rise in the apoptosis in endometrial
glands in the secretory phase is unlikely to be regulated
at the receptor level since the TNF-c~ receptor expression in endometrium is not menstrual cycle-dependent,
but its expression progressively diminished from the
basalis towards the upper functionalis [228]. The
amount of TNF-ot released into the culture medium by
the human endometrium is low in the proliferative phase
and progressively increases in the secretory phase peaking during menstruation [228].
Others authors, using in situ hybridisation and Northern blotting, have shown that TNF-ot mRNA is not
detected during the proliferative phase and that the level
increases during the secretory phase. They identified
TNF-ct m RNA only in the wall of coiled arteries. While
TNF-o~ was detected both in the wall of coiled arteries
and, in highest concentration, within the epithelial cells,
TNF-o~ might be secreted by the cells from the wall
arteries and subsequently captured and concentrated by
epithelial cells. TNF-a might be responsible for a break
of the coiled arteries resulting in haemorrhagic necrosis
observed in the menstruating endometrium. According
to this hypothesis, TNF-ct-induced apoptosis might be
an epiphenomenon [236].
Apoptosis has been detected in decidual tissue regression and reorganisation. Apoptotic cell death occurs
despite high levels of plasma progesterone and high levels of progesterone receptors [237]. Transforming
growth factor-0, detected just after implantation, is
suspected to be involved in this decidual apoptosis [135].
7. Apoptosis and ovary
Just before ovulation, there is a progressive increase
in apoptotic cells within the ovarian surface epithelium
at the avascular site of rupture [238].
Atresia is a prominent feature of ovarian follicular development in all mammalian species. In the ovary, greater than 99% of the follicles present at birth are destined
to undergo atresia during life. In humans, less than 400
of the more than 400 000 follicles found at the puberty
will achieve ovulation whereas the great majority of the
follicles undergo atresia. The corpora lutea is one the
fastest growing tissues in the adult female and also one
of the few adult tissues that exhibit periodic growth and
regression. Granulosa cells and theca interna cells collected from preovulatory follicles destined to atresia and
from post ovulatory follicles display the internucleosomal fragmentation of DNA characteristic of
cells undergoing apoptosis [239-243]. The healthy
follicles, whatever their development stage, never
display evidence of apoptosis. Just after ovulation, apoptosis is detected beside proliferation in the developing
corpora lutea (CL) [244,245]. Granulosa and luteal cells
94
D. Vinatier et al./ European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 85-102
are equipped with Ca2+/Mg2+-dependent endonuclease
activity whose regulatory factors are numerous in the
ovary [246].
Three theoretical models can be envisaged for the
determination of follicle fate. (1) The follicles undergoing atresia may be predetermined by inherent deficiency
of the oocyte, follicle cells or their immediate environment. (2) Most, if not all, follicles are capable of
reaching ovulation unless atresia is triggered by
atretogenic stimuli. As discussed below, androgens,
GnRh-like substances and, perhaps, IL-6 are potential
candidates as intraovarian atretogenic factors. (3) The
normal fate of all follicles is atresia. Only follicles
reaching a specific stage of development, coinciding
with critical hormonal signals, are spared atresia. Thus
the fate of the follicle cells is always death either before
ovulation or during regression of corpora lutea.
Enzymatic dispersion of intact corpus luteum induces
a rapid initiation of endonuclease activity and apoptotic
cell death, suggesting that the dispersed cells have lost
their survival signal [247]. Moreover, after 24 h of culture, the proportion of apoptotic granulosa cells was
two-fold lower for aggregated cells compared with single
granulosa cells. Aggregated granulosa cells are connected by gap junction [248].
Apoptosis of atresic follicle is associated with defective production of oestrogens and of proteins necessary
for the maintenance of follicle integrity (FSH and LH
receptor, aromatase). The follicular fluid oestrogens
level is correlated to the extent of apoptosis [245].
Gonadotropins and gonadal steroids have been shown
to modulate the incidence of apoptose [249,250]. Treatment of rats with Nembutal blocks the preovulatory
surge of gonadotropins and results in advanced atresia
within 3-4 days [251]. Deprivation of gonadotropins by
hypophysectomy results in atresia of preovulatory
follicles that is avoidable by FSH treatment [251].
Gonadal steroids are efficient regulators of ovarian
apoptotic cell death. Oestrogens treatment inhibits,
whereas androgens stimulates [250,252]. Progesterone
acting through the progesterone receptor inhibits
granulosa cell apoptosis [248].
In te ovary, the presence of a complete IGF system
(insulin-like growth factor), including ligands, receptors
and binding proteins, has been demonstrated [253].
Granulosa cells are likely sites of IGF-I production,
reception and action [254]. Treatment of rat with IGF-I
alone suppresses granulosa cell apoptosis.
The IGF-I effects on follicle apoptosis migr't be mediated by specific IGF receptor type whose ovarian concentration is increased by FSH and LH treatment.
Cotreatment of IGF-I and FSH has no additional effect
on apoptosis suppression. IGF-I should be mediator of
gonadotropins because treatment with FSH and
IGFB-3, an IGF-binding protein, does not suppress
apoptosis [255,256].
Treatment of cultured granulosa cells with epidermal
growth factor (EGF)/transforming growth factor-or
(TGFo0 inhibits the spontaneous occurring apoptosis
[257]. The presence of EGF/TGFo~, basic fibroblast
growth factors (bFGF), and their receptors has been
demonstrated in the preovulatory human follicles [258]
and in human corpus luteum [259]. mRNAs encoding
TGFot are upregulated in follicular cells after FSH stimulation in vivo [260]. While TGFo~ protein has been
localised in the theca-interstitial layer of follicles and
granulosa cells in both rat [260] and bovine [2611 species, high affinity receptors for EGF/TGFot [25] and
bFGF have been localised to granulosa cells, suggesting
an inhibition of apoptosis of granulosa cells of follicles
selected for ovulation by the paracrine and autocrine action of EGF/TGFa and bFGF produced by the thecainterstitial and granulosa cells.
GnRh receptors are found in granulosa cells. GnRH
and agonists inhibit many of the effects elicited by FSH
that are associated with follicular maturation and promote follicular apoptosis [262]. The effects of GnRH
treatment on DNA fragmentation are blocked by the
specific receptor blocker [262]. The action of GnRH on
endonuclease activity is mediated through a
Ca2+-dependent pathway, because GnRh has been
shown to increase intracellular Ca 2+ levels [263].
bcl-2 family are expressed highly in the gonads (264,
265). Ablation of bcl-2 expression by transfection of
mice decreases the number of oocytes and primordial
follicles. Additionally, the remaining primordial follicles
contain only a single layer of granulosa cells without
oocyte [266]. Introduction of bcl-2 protein in the egg of
Xenopus in culture delays the apoptosis [64]. The inhibitory effect on apoptosis of gonadotropins is associated with a marked reduction in bax expression which
effectively tip the ratio of death repressor (bcl-2/bclxlong) death inducer (bax/bcl-xshort) in favour of higher
death repressor levels. [265].
The tumour suppressor p53 is expressed in granulosa
cells. The expression of this gene is reduced by treatment
with exogenous gonadotropin in vivo. Apoptosis
observed in antral follicles induced in serum-free medium is associated with a significant increase in p53
mRNA levels compared to those in freshly-isolated
follicles without apoptosis. This observation suggests a
strong correlation between apoptosis and expression of
p53 in the ovary [265]. Concomitant with the loss of
apoptotic granulosa cells observed to occur after in vivo
gonadotropin treatment, the levels of p53 were reduced
to undetectable levels !~ ~",-adotropin~primed ovaries.
The expression of bax, a target for p53 t,p-;egulation, is
also markedly reduced in rat granulosa cells after in vivo
treatment with gonadotropins [267]. It is possible that
the loss of p53 may contribute to decreased expression
of the cell death-promoting factor, bax [265].
The ovary should be the unique site of expression of
D Vinatier et al./European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 85-102
WT-1 gene (Wilms' tumor suppressor gene) [268,269].
Similar to p53, gonadotropin-induced follicular survival
is associated with a significant reduction in ovarian
WT-I protein [265]. It is possible that WT-I serves to
amplify the actions of p53 in granulosa cells [270]. WT-1
has also been reported to repress transcriptional activity
of genes encoding several growth factors and their
receptors [257,271,272]. Based on the reported importance of these growth factors as mediators of
gonadotropin-promoted follicular survival, WT-1 may
act directly during atresia to downregulate the expression of these survival factors and their receptors within
the follicle.
The generation of reactive oxygen species in cells may
play a fundamental role in the initiation of apoptosis
[273-275]. Reactive oxygen species are by-products
generated in cells through normal metabolic activity,
hormone-mediated phospholipase activity and lipid
peroxydation. Neutrophils arriving in the aging corporea lutea release oxidative-free radicals. Oxidativefree radicals induced apoptosis of granulosa cells and
endothelial cells. Treatment of follicles with superoxyde
dismutase (SOD), which protect the cell from oxidative
stress, inhibits apoptosis induced by serum deprivation.
Gonadotropin treatment of ovaries during 2 days inhibits apoptosis of granulosa cells, while it stimulates
superoxyde dismutase activity [265].
The ovarian existence of a IL-l system complete with
ligands, receptors and a receptor antagonist is now well
established. Using cultures of preovulatory rat follicles,
it has been shown that ILl-fl suppresses follicle apoptosis [271]. Nitric oxide (NO) also inhibits apoptosis. It is
suggested that the apoptosis-suppressing action of IL-1
is mediated by endogenous NO production. This hypothesis is supported by the finding that the suppressive
effect of IL-1 is partially blocked by the addition of an
inhibitor of NO synthetase. The administration of an
ovulatory dose of hCG increases IL-lfl gene expression
in rat ovarian thecal-interstitial cells and also increases
follicular NO production. The suppressive effects of
gonadotropins are partially reversed by IL-1RA (IL-1
receptor antogonist) implying that the effects of
gonadotropins are partially mediated via endogenous
IL-1 /~.
Several genes of the ICE family (Interleukin-l-~converting enzyme) are expressed in the ovary. The
products of these genes (ICE, Ich-1 and CPP32) are involved in apoptosis. They are responsible of the degradation of two key proteins involved in maintaining
cellular homeostasis. Gonadotropin treatment of rat
follicles significantly decreases the level of transcription
of Ich-1 and CPP32. The treatment with specific inhibitors of these two proteases inhibits DNA degradation by Ca 2+/Mg 2+-dependent endonuclease [276].
The Fas antigen termed APO-1 is a transmembrane
surface protein. The intracytoplasmic domain of Fas
95
contains a death domain that is required for signalling
of cell death. The induction of apoptosis of the cell carrier occurs when Fas antigen is engaged with specific
ligand. Granulosa cells and oovocyte of atretic follicles
express Fas antigen [277,278]. Interferon 3' (IFN 3,) induces Fas expression in granulosa and luteal cells. Binding of antibodies to Fas antigen induces granulosa cells
apoptosis [278]. The ligand to the Fas antigen is expressed on CD8+ T lymphocyte (cytotoxic T cell, CTLs)
[279]. After ovulation, T cells are present in the antral
follicle, in those in regression, and in the corpora lutea.
The follicular lymphocytes appear to be selected, as it is
the CD8+ T cells which predominate. The activated T
lymphocytes release interferon 3,. Interferon 3, attracts
and activates the monocytes/macrophages which secrete
and induces the expression of class II MHC antigens on
granulosa and luteal cells. Combinations of interferon 3'
and TNF ot induce apoptosis of luteal cells [280] either
by their increased production of prostaglandin F2a
(PGF2a) [281] or by their increased synthesis of nitric
oxide [282].
The expression of class I antigens seems to play a role
in luteolysis for these antigens are mildly expressed in
luteal corpus luteum while they are strongly expressed in
aging corpora luteum. Fas antigen may provide a link
between immune and endocrine system. During regression of corpora lutea and follicle atresia, CD8+ T lymphocytes are attracted locally. They release IFN 3' which
has several functions: (1) it attracts and activates macrophages; (2) it induces expression of Fas and class I MHC
antigen. All the actors of apoptotosis are ready. CD8+
T cell binds class I MHC antigen via its antigen receptor
(TCR). Fas protein connects its ligand. These two
signalling pathways induce granulosa cell apoptosis and
CD8+ cell death avoiding expansion of CD8+ T cells.
IFN 3,-activated macrophages can ingest the two apoptotic cells.
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