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School of Surgical and Reproductive Sciences, The Medical School, The University of Newcastle, Newcastle upon Tyne, NE2 4HH, United Kingdom
Address all correspondence and requests for reprints to: James I. Gillespie, School of Surgical and Reproductive Sciences, The Medical School, The University of Newcastle, Newcastle upon Tyne, NE2 4HH, United Kingdom. E-mail: j.i.gillespie{at}ncl.ac.uk
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Abstract |
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Introduction |
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It is likely that the expression of CAPs is regulated by signals acting on the myometrial cells. At present, the nature of these signals is poorly understood. The control of the gap junction protein, connexin 43 (Cx43), has been studied in vitro in some detail (9, 10, 11, 12, 13, 14). High estrogen and low progesterone concentrations increase Cx43 expression (11), as does exposure to phorbol ester (13). Thus, Cx43 gene expression appears to be regulated by changes in the estrogen/progesterone ratio working through the activation of protein kinase C (11, 12, 13). The processes involved in the activation of other CAP genes are less well understood. The ryanodine-sensitive intracellular Ca2+ release channel protein (RyR2) is a CAP that, in vitro, can be up-regulated by transforming growth factor-ß1 (TGFß1) (7). This has led to the idea that TGFß1 could be playing a similar role in the activation of the RyR2 gene in vivo. Recent data have shown that total TGFß1 levels are increased in pregnant nonlaboring myometrium compared with nonpregnant tissue, and the levels are further increased in spontaneously laboring tissue (15). In addition, the expression of TGFß receptor types I and II are also increased in the pregnant nonlaboring myometrium, but both receptors are down-regulated in the laboring tissue (15). These observations suggest that TGFß is part of a signaling system that may be responsible for the activation of specific CAP genes in vivo.
There is some evidence for the involvement of cytokines in the
modulation of uterine function in premature labors involving infection
(reviewed in Ref. 16). It is thought that activated leukocytes release
a number of cytokines and chemokines including interleukins IL-1, IL-6
and IL-8, tumor necrosis factor (TNF
), and TGFß. The end result of
this cytokine activation is an increase in the local concentration of
prostaglandin, which in turn has complex actions on the myometrium and
cervix (16, 17, 18, 19). The resulting strong myometrial contractions, along
with cervical softening, can initiate premature labor and subsequent
delivery (16, 17, 18, 19).
Because TGFß and TGFß receptor expression change in late pregnancy in a way consistent with a cytokine signaling system playing a part in CAP activation, this raises the question: "What signals and events might influence the expression of TGFß and TGFß receptors?" Based on the measurements of cytokine expression in infection induced premature activation of the myometrium, one possibility is that other cytokines might influence the expression of TGFß and TGFß receptors. It has been shown that the concentrations of IL-1 and IL-8 are increased in the human myometrium at term (20, 21). The receptors for IL-8 have also been demonstrated in myometrial samples before the initiation of labor (22). However, there are no data to assess the possibility that the myometrium expresses receptors for IL-1 or whether the expression levels of both IL-1 and IL-8 receptors change with gestation. We have measured the expression of IL-1 and IL-8 receptors in nonpregnant, pregnant nonlaboring, and spontaneously laboring human myometrium and report differences in expression with gestation. To determine whether TGFß and TGFß receptor expression can be altered, we have utilized myometrial smooth muscle cells maintained in vitro. The data suggest that TGFß and TGFß receptor type I are affected by steroid hormones and IL-8 and that IL-8 receptor expression can be altered by TGFß. These observations suggest that a complex cascade of cytokine interactions under hormonal control may be involved in the final stages of preparation of the myometrium at term.
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Materials and Methods |
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Tissue collection
Samples of myometrium were taken from the lower uterine segment
from patients undergoing hysterectomy (nonpregnant, n = 17),
elective cesarean section (pregnant nonlaboring, n = 9), or
emergency cesarean section (spontaneous laboring, n = 9). This
investigation had the ethical approval of Newcastle Area Health
Authority, and informed consent was obtained from all patients. The
clinical indication for hysterectomy in nonpregnant women was benign
gynecological disorders such as menorrhagia and myoma uteri. Cesarean
sections at term (38–40 weeks of gestation) were performed due to
previous sections or cephalopelvic disproportion. For emergency cases
where labor had progressed to the active stage with the cervix 7–10 cm
dilated, the diagnosis was fetal distress. In this group, amniotic
membranes were intact, and no history or presence of infection was
noted. The samples were excised about 5 mm away from the decidua,
serosal layer, tumor, washed in PBS, cut into small pieces and frozen
at -70 C until required.
Preparation of tissue lysates
Three groups of samples (nonpregnant, pregnant nonlaboring, and
spontaneous laboring samples) were used. Frozen tissues were
homogenized in 3 vol cold homogenizing buffer, pH 7.6, (23) containing
25 mM Tris-base, 0.25 M sucrose, 1
mM EDTA, 5 µg/ml pepstatin, 5 µg/ml leupeptin, and 5
µg/ml aprotinin. The homogenate was then centrifuged at
1,500 x g for 30 min at 4 C. The supernatant was
removed and recentrifuged to obtain a clear lysate. The protein content
in tissue lysates was determined by the method of Bradford (24) using
the protein assay kit form Bio-Rad Laboratories, Inc..
Aliquots of samples were rapidly frozen and kept at -70 C until
required. All procedures were carried out at 4 C.
Cell culture
Human myometrial smooth muscle cells were prepared from the
lower uterine segment of nonpregnant myometrium using a modification of
the technique described by Morgan et al. (25). Briefly, the
myocytes were obtained by short-term
collagenase/elastase/deoxyribonuclease digestion at 37 C with
agitation. The isolated myocytes were cultured to confluence in a
humidified atmosphere at 37 C in 75 cm2 flasks containing
Medium 199 with 10% FCS, 1% (vol/vol) glutamine (200 mm), 500 U
penicillin, 100 µg/ml streptomycin, and gassed with 5%
CO2. Experiments were performed on confluent cells in 25
cm2 flasks or 12-well plates from subcultures number 1 to
6. The cultured cells were treated with or without TGFß1 (1 ng/ml),
IL-1 (10 ng/ml), IL-8 (150 ng/ml), 17ß-estradiol (10 and 100
nM), and progesterone (100 and 200 nM) in serum
culture media for 24 h. The myocytes were washed at the end of
each treatment with HBSS without Ca2+, harvested with
trypsin-EDTA, and washed once with HBSS without Ca2+ and
centrifuged at 1200 rpm for 5 min. The pellet was lysed in homogenizing
buffer, and protein content was measured. Aliquots of cell homogenates
(50 µg) were kept at -70 C.
Western blot and immunoblot analysis
Myometrial tissue lysates or cultured-cell homogenates (50 µg)
were solubilized in an equal volume of Laemmli (26) sample buffer
containing 4% SDS with 10% ß-mercaptoethanol and boiled for 5 min.
All samples were then electrophoresed on 7.5% polyacrylamide gel at 30
mA in a mini-PROTEAN II cell (Bio-Rad Laboratories, Inc.).
Proteins from the gels were electro-transferred onto nitro-cellulose
membrane (0.45 µm) using a Bio-Rad semidry blotting
apparatus with 25 mM Tris, 0.195 M glycine, and
20% (vol/vol) methanol transfer buffer, pH 8.6 (23) at 15 V for 1
h 15 min. The nitro-cellulose strips were blocked overnight in
Tris-buffered saline with Tween (TBST: 10 mM Tris-HCl, 150
mM NaCl, pH 8, and 0.05% Tween 20) containing 5% nonfat
dried milk. The blots were washed three times with TBST and were
incubated with TBST containing 1% milk and primary antibodies specific
to TßRI and IL-1RI at 0.5 µg/ml (1:200 dilution) and 2 µg/ml
(1:100), respectively for 3 h at room temperature while being
constantly shaken. Antibody to IL-8RB was used at a concentration of
0.5 µg/ml (1:400 dilution) for 2 h and 30 min. Goat antirabbit
horseradish peroxidase-conjugated secondary antibody in TBST was
applied to the blots at a dilution of 1:2500 for 1 h after three
15-min washings. The blots were then washed and the immunoreactive
bands were developed with an ECL system. Immunoblottings were repeated
at least twice on each tissue with similar results. The molecular
weight of the immunoreactive bands was determined using molecular
weight standards from Bio-Rad Laboratories, Inc.
Quantification of immunoreactive bands
The images of immunoreactive staining were measured by a GS 690
Imaging Densitometer and analyzed by the MultiAnalyst PC software from
Bio-Rad Laboratories, Inc.. Data for the expression of
receptors in the myometrium in each group represents the mean and
SEM from eight independent samples. In cultured myometrial
cell experiments, the levels of receptor expression are calculated from
the mean of duplicates from four to eight different tissue samples. The
values of receptor expression in the myometrium and in cultured cells
are expressed as a percentage of the values obtained from the
nonpregnant myometrium and non treatment control cells,
respectively.
TGFß1 immunoassay
The total level of TGFß1 in cultured myometrial smooth muscle
cells was assayed using a TGFß1 ELISA system. Smooth muscle cells
were cultured in 12-well plates in the presence of 10% FCS until
confluent and washed with HBSS. The cells were then incubated with or
without IL-1 (10 ng/ml), IL-8 (150 ng/ml), 17ß-estradiol (10 and 100
nM), progesterone (100 and 200 nM), and
combination thereof except progesterone in serum culture medium for
24 h. The medium to be assayed for TGFß1 were collected and
centrifuged at 1000 x g for 10 min at 4 C to remove
particulates and stored at -70 C until used. The assay procedures were
carried out in duplicate according to the protocol provided. These
involved the activation of latent TGFß1 to the active form by acid
hydrolysis and thus the total levels of TGFß1 in the culture
supernatants were determined. Measurement of TGFß1 in supernatants
from cells grown in the same medium without any treatment was used as
control. The concentration of cytokine was calculated from the linear
regression analysis obtained from the log of TGFß1 concentrations
vs. the log of optical density standard curve. The mean of
total TGFß1 concentration is reported as pg/µg protein of
cells.
Statistical analysis
Data are expressed as mean ± SEM. Comparisons
between two groups were analyzed with Student’s t test.
Multiple comparisons were performed using ANOVA with a Bonferroni post
test. Differences with P values < 0.05 were considered
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows typical Western blots using
antibody against the IL-1 receptor on samples of NP, P, and SL tissues.
Figure 1B shows accumulated data from a densitometric analysis,
obtained from eight tissue samples in each group. The highest level of
IL-1 receptor type 1 expression was found to be in the NP samples.
Compared with the nonpregnant tissue, the receptor expression was
significant reduced to 71 ± 8% (P < 0.05) and
40 ± 7% (P < 0.001) in the P and SL samples,
respectively. There was also a significant difference in the expression
levels between the pregnant and spontaneously laboring tissue
(P < 0.01).
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shows an example of a Western
blot examining the expression of IL-8 receptor type B in the same group
of myometrial samples. As can be seen in Fig. 2B, in contrast to the
IL-1 receptor, the expression of IL-8 receptor type B is highest in the
pregnant nonlaboring samples (196 ± 24% of the NP level). In the
spontaneously laboring myometrium, the expression of IL-8 receptor was
found to be reduced to 59 ± 10% compared with the nonpregnant
control. It may be important to note that the patterns of change in
receptor expression are different for IL-1 and IL-8. The changes in
expression of the IL-8 receptor are similar to those previously
reported for the TGFß receptors (15). In addition, IL-1 and IL-8 have
been demonstrated in the myometrium (21). These data, taken together
with published data, show that the levels of cytokine receptors for
IL-1, IL-8, and TGFß change in the myometrium during pregnancy,
suggest that these systems may play a role as autocrine signals that
prepare the myometrium for term.
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The effect of IL-1 and IL-8 on TGFß1 and TGFß receptor type 1
expression
Figure 3, A and B, shows that in the
presence of FCS, IL-8 in a dose chosen from a dose range that stimulate
transient mobilization of Ca2+ in human keratinocytes (30)
significantly increased the expression of both TGFß1 and TGFß
receptor type I in myometrial cells in vitro. IL-1 at a dose
chosen to be maximal for prostaglandin stimulation in human myometrial
cells (31, 32) significantly increased the total level of TGFß1 but
did not significantly influence the expression of its receptor. Because
IL-8 affected both TGFß1 and TGFß receptor type I expression,
further experiments were performed to explore the possible interactions
between the TGFß and IL-8 signaling systems.
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) in
myometrial cells exposed to TGFß1 (1 ng/ml) for 24 h. In
contrast, in cells exposed to TGFß1 the TGFß receptor type I was
markedly increased (Fig. 4B). When cells were exposed to IL-8 (150
ng/ml) the expression of the IL-8 receptor type B was found to be
reduced (Fig. 4C). Thus, there appears to be a complex relationship
between these cytokines and the expression of cytokine receptors.
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. Estrogen at 10 nM had
no effect on TGFß1 level, but at 100 nM TGFß1 level was
significantly increased from the control level of 20.7 ± 1.3
pg/µg protein to 29.2 ± 0.6 pg/µg protein. In contrast,
progesterone at 100 nM increased significantly TGFß1
level to 26.2 ± 1.3 pg/µg protein compared with the control,
although there was no significant increase detected on exposure 200
nM progesterone (Fig. 5A).
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). The percentage
reductions following estrogen and progesterone exposure were 61.4
± 10.5 and 47.8 ± 9.5, respectively.
In vivo it is likely that there may be changes in both
steroid hormone levels as well as cytokine concentrations. In Fig. 3 it
was shown that IL-1 and IL-8 alone significantly increased the release
of TGFß1 into the culture medium. Figure 6 illustrates data that begin to examine
the combined effects of IL-1, IL-8, and estrogen. Estrogen at 100
nM reduced the stimulatory effect of IL-1 and IL-8 on the
release of TGFß1. When IL-1 and IL-8 were added simultaneously, there
was an increase in TGFß1 release compared with control, but this was
significantly lower than the stimulation produced by IL-8 alone
(32.7 ± 1.7 compared with 54.7 ± 2.0 pg/µg protein).
Thus, it appears that estrogen can inhibit the action of the cytokines
in vitro and that IL-1 can interfere with the stimulatory
effect of IL-8. The consequences of these complex interactions in
vivo have yet to be explored.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The intracellular Ca2+ release channel protein (RyR2) is a CAP whose expression increases in vivo at term and which in vitro can be up-regulated by TGFß1 (7). This has lead to the suggestion that TGFß1 could be playing a similar role in the activation of the RyR2 gene in vivo. TGFß1 levels are increased in pregnant nonlaboring myometrium compared with nonpregnant tissue with a further increase in spontaneously laboring tissue (15). In addition, the expression of TGFß receptor types I and II is also increased in pregnant nonlaboring myometrium, but both receptors are down-regulated in laboring tissue (15). These observations suggest that TGFß may form part of an autocrine signaling system within the myometrium in vivo.
There are several reports showing that TGFß, TNF, IL-1, and IL-8
are present within myometrial cells and that the concentrations of
these cytokines increase toward term (15, 20, 21). The data presented
here demonstrate that the receptors for IL-1 and IL-8 are present in
myometrial tissue. Importantly, the levels of expression of the IL-1
and IL-8 receptors change. These observations support previous
observations that IL-8 receptors are present in the human myometrium at
term before the initiation of labor; however, in this previous study
there was no estimate of the level of receptor expression (22).
There also appears to be a difference in the timing of the changes in expression of IL-1, IL-8, and TGFß receptors. IL-1 receptor expression is greatest in the nonpregnant tissue, lower in the nonlaboring tissue, and lowest in the spontaneously laboring tissue. In contrast, IL-8 receptor expression is maximal in nonlaboring myometrium and falls in laboring myometrium. The pattern of changes in IL-8 receptor expression is similar to that reported for TGFß1 receptors (15). The particular relevance of these changes to overall myometrial functioning at term has yet to be established. However, it may be speculated that the changes reflect a complex series of autocrine signals taking place within the myometrium. These autocrine signals form part of a cascade of events leading to the eventual differentiation of the myometrium in preparation for powerful contractions at term. If this were the case the myometrium would, to a great extent, be able to control its development without overt intervention from other fetal or maternal systems.
There has been considerable interest in the nature of premature myometrial activity and a role for uterine infection (16, 36). Cytokines released by leukocytes in this pathological condition are thought to trigger the expression of factors such as prostaglandins that subsequently induced myometrial activity (17, 18, 19). The data presented here suggest that the autocrine expression of cytokines within the myometrial smooth muscle may form part of a physiological process that is involved in the preparation of the myometrium for term. If the idea of an autocrine physiological signaling cascade is correct, then it is not surprising that exogenous cytokines originating from infection induced leukocytes can pathologically and prematurely activate the cascade.
It is therefore important to understand the complexities of these autocrine signaling events and the interactions between these signaling associated proteins (SAPs). It is not possible to interfere with the pregnant myometrium in vivo. Thus, an alternative approach is to use human myometrial cells in vitro. In the present study, both IL-1 and IL-8 increase TGFß1 production in human myometrial cells in culture. IL-1 and IL-8 also increase the level of TGFß receptor type 1 (TßRI) expression although, IL-8 appears to be more effective than IL-1. Thus, under these conditions, both cytokines affect the steady state level of both TGFß1 and its receptor.
In endometrial cells, the level of IL-8 messenger RNA can be increased
by TGFß (37). It has been found in this study that TGFß1 inhibits
the expression of IL-8 receptor type B (IL-8RB) in isolated myometrial
cells. The level of IL-8RB expression in the myometrial cell in
vitro is also down-regulated by IL-8 itself (see Fig. 4C). This
IL-8 induced down-regulation of its own receptor has also been reported
in other cell types (38). One possible interpretation of these data
would be that the TGFß signaling system is the end point of a
cascade. IL-8 would be activated at an earlier stage such that IL-8
would stimulate TGFß production and TGFß receptor expression.
TGFß would increase its receptor expression, providing a positive
feedback to establish the TGFß signaling pathway. TGFß would also
down-regulate the IL-8 system, thus decreasing its effectiveness. In
this way one cytokine signal would decrease while another would
increase in importance.
In human endometrial cells, TGFß1 acts to potentiate the effect of
IL-1 to increase the level of IL-8 gene expression (37). There is
evidence that IL-1 and TNF can regulate the level of IL-8 production
in human endometrial cells in culture (39) and in human hepatoma cells
(40). It is reasonable to hypothesize that the levels of IL-8 in human
myometrial smooth muscle cells can be increased by IL-1 and TNF. By
using the in vitro model, it can be suggested that there is
an interaction between cytokines IL-1, IL-8, and TGFß1 in human
myometrium at term before labor begins. The sequence of events in the
myometrium may be initiated when IL-1 induces IL-8, IL-8 induces TGFß
and its receptor, and finally TGFß1 up-regulates the expression of
CAP genes.
Exposure to IL-1 results in an increase in prostaglandin synthesis in human myometrial cells, presumably by induction of COX2 (32). TGFß1 can increase the synthesis of COX2 and endothelin-1 in other cell types (41, 42). The expression of COX2 in human myometrial smooth muscle was found to be increased by TGFß1 (Hatthachote and Gillespie, unpublished observations). Thus, there appears to be a complex interplay between cytokines that can act to promote the expression of CAPs and the expression of SAPs.
Previous reports have suggested that the TGFß1 signaling system may be involved in an autocrine role in the human myometrium (15). The data presented in this paper point to the possibility that IL-1 and IL-8 play a similar autocrine role.
The levels of expression of cytokines can also be regulated by sex steroids. This study shows that estrogen and progesterone can induce TGFß1 synthesis in human myometrial cells. Progesterone is less effective on TGFß1 synthesis compared with estrogen. In contrast, it has been shown that synthetic progesterone [medroxyprogesterone acetate (MPA)] increased the total level of TGFß1 in human myometrial cells more than estrogen (43). One possibility that may account for the different responses to MPA and progesterone in human myometrial cells may be a consequence of the cells metabolizing progesterone to a form that does not bind to the progesterone receptor (44). In contrast to parturition in many animals, plasma concentrations of estrogen and progesterone do not fall before the onset of labor in human. There is one report that suggests that TGFß may act like an antiprogestin (45). If this is correct, then a high level of TGFß in the myometrium at term may inhibit the actions of progesterone. Thus, inhibition of progesterone action, rather than a withdrawal of progesterone, may be involved with the changes seen in uterine activity before labor.
An increase in the total level of TGFß1 has been observed in human term pregnant myometrium (15). In this case, the effect of estrogen, IL-1, and IL-8 may act separately or in concert to overcome the inhibitory effect of a high level of progesterone on TGFß1 production. The present study has shown that high dose of estrogen and cytokines alone and in combination were more effective in increasing the total level of TGFß1 than was progesterone. This would support the hypothesis that these events occur in the myometrium in vivo.
Estrogen and progesterone also affect the level of TßRI expression. In contrast to the stimulation effect of estrogen on TGFß1, estrogen acts to decrease the expression of TßRI in human myometrial cells as does progesterone. This is in keeping with the observation in vivo that the level of expression of TßRI is reduced in spontaneously laboring myometrium at a time when the plasma levels of both steroids are high. Thus, the expression TßRI and TGFß1 are regulated in the opposite way by sex hormones in human myometrium. These findings also suggest a network of endocrine and autocrine systems in human myometrium.
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Acknowledgments |
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Footnotes |
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Received October 26, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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selectively stimulates prostaglandin
F2 production by macrophages in human term decidua.
Am J Obstet Gynecol 167:815–820[Medline]
, and epidermal growth factor on prostaglandin production in
human chorion cells. Am J Reprod Immunol 30:146–153
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factor-ß exhibit differential kinetics on endothelin-1 synthesis in
amnion cells. J Soc Gynecol Invest 5:25–30[CrossRef][Medline]
-dihydroxyprogesterone
(5-pregnane-3,20-dione) in women and men. J Clin Endocrinol
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