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Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois 60212-7313
Address all correspondence and requests for reprints to: Asgi T. Fazleabas, Ph.D., The University of Illinois at Chicago, Department of Obstetrics and Gynecology, 820 South Wood Street (M/C 808), Chicago, Illinois 60612-7313. E-mail: asgi{at}uic.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B-
. This suggests that IL-1ß induces
multiple signaling pathways in stromal cells that result in the
activation of mitogen-activated protein kinase cascade and the
transcription factor NF-B. After 4 h of stimulation, IL-1ß
induced gene expression of cyclooxygenase-2 (COX-2) but not
cyclooxygenase-1 (COX-1). PGE2 synthesis paralleled COX-2
messenger RNA expression. The addition of hormones [36 nM
estradiol-17ß, 1 µM medroxyprogesterone acetate, and
100ng/ml relaxin] to IL-1ß-treated cells induced insulin-like growth
factor binding protein-1 (IGFBP-1) messenger RNA expression after 3
days of incubation. A specific COX-2 inhibitor, NS 398 (10
nM), partially inhibited IGFBP-1 protein synthesis. In
contrast, the induction of IGFBP-1 by N6,
2'-O-dibutyryladenosine 3:5'-cyclic monophosphate
(dbcAMP) and hormones was not affected by NS 398 treatment. Both dbcAMP
and IL-1ß, in the presence of hormones, can independently induce
IGFBP-1 gene expression and decidualization. However, if IL-1ß and
dbcAMP were added together, IGFBP-1 expression was inhibited. These
data suggest that IL-1ß can activate multiple signaling pathways that
either positively or negatively regulate IGFBP-1 gene expression and
decidualization. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Using a simulated pregnant baboon model, we demonstrated that exogenous CG, in conjunction with estrogen and progesterone, can initiate functional changes in uterine endometrium that are comparable with those seen during early pregnancy (2, 6). However, the hormone treatments alone were not sufficient to complete the decidualization process, suggesting the involvement of a conceptus factor (7, 8).
Implantation has been characterized as an inflammatory type response. A number of cytokines have been identified at the implantation site. Interleukin (IL)-1 was identified as one such paracrine factor that modulates the communication between the maternal endometrium and embryo (9, 10).
The cyclooxygenase (COX) enzymes required for PG biosynthesis exist in two isoforms (constitutive COX-1 and inducible COX-2). Studies using COX-2 null mice show reproductive failure at ovulation, fertilization, implantation, and decidualization (11). In the baboon endometrium, with the onset of pregnancy, COX-2 is expressed specifically in the stromal cells at the site of implantation (12). IL-1 regulates COX-2 gene expression in a variety of cell types, including stromal fibroblasts (13, 14).
Therefore, the purpose of our study was to evaluate the role of IL-1 as a component of the decidualization process. Specifically we chose to study its ability to induce signal transduction and regulate COX-2 and IGFBP-1 expression in stromal fibroblasts isolated from baboons. Comparative studies were also done with human stromal fibroblasts (HuF).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B-
(Ser32), IB- antibodies were from New England Biolabs, Inc. (Beverly, MA). The selective inhibitor of
COX-2, NS-398 [N-(2-Cyclohexyloxy-4-nitrophenyl)
methanesulfonamide] was from Calbiochem (San Diego, CA);
N6, 2'-O-dibutyryladenosine 3:5'-cyclic
monophosphate (dbcAMP) was from Sigma (St. Louis, MO). All
cell culture supplies were obtained from Life Technologies, Inc. (Gaithersburg, MD). Other reagents of cell culture grade
were purchased from Fisher Scientific (Itasca, IL),
Sigma (St. Louis, MO), or Roche Molecular Biochemicals (Indianapolis, IN).
Isolation of baboon stromal cells
Midluteal phase (9–12 days post ovulation) endometrial tissue
was obtained from adult female baboons (Papio anubis)
by endometrectomy or after hysterectomy. All animal studies were
approved by the Animal Care Committee at the University of Illinois at
Chicago. Stromal cells were isolated from baboon endometrial tissues as
described in detail previously (8).
Isolation of human fibroblast cells
Decidualized uterine endometrium maintains a proliferating
population of fibroblastic cells, which closely resemble the stromal
cells (15, 16). HuF were isolated from decidua parietalis
dissected from the placental membranes after normal vaginal delivery at
term. These studies were approved by the Institutional Review Board of
the University of Illinois. Briefly, scraped cells were digested in
0.1% collagenase, 0.02% deoxynuclease in calcium- and magnesium-free
HBSS. Cells were isolated in the same manner as described previously
for baboon stromal fibroblasts (8). Cells were plated in
four 100-mm culture dishes (Becton Dickinson and Co. Labware, Franklin Lakes, NJ) and placed into an
incubator at 37 C, 5% CO2. The next day, the
plates were extensively washed with PBS to remove nonadherent (mainly
decidual) cells. At confluence, cells were trypsinized and used for
experiments in passage number 3–5. Cell purity was assessed by
immunocytochemistry using antibodies against cytokeratin (DAKO Corp., Carpenteria, CA), vimentin (Zymed Laboratories, Inc., San Francisco, CA). The purity of the fibroblast cell
preparations used in studies was more than 95%.
Treatment of cells
Experiments were performed when the baboon stromal cells or HuF
cells reached 80–90% confluence. Culture medium was changed into
serum-free culture medium for the 1-, 4-, and 24-h time points or into
2% stripped FBS culture medium for longer incubation times. The drug
treatments are indicated in figure legends. Cell culture medium was
changed every 2 days. Twenty-four hours before final experimental end
point, the medium was changed into serum-free culture medium. The word
"hormones" in this paper includes treatment with a mix of (final
concentration) 36 nM estradiol-17ß, 1 µM
medroxyprogesterone acetate, and 100 ng/ml highly purified porcine
relaxin.This concentration of relaxin does not significantly
increase intracellular levels of cAMP after 15 min of incubation
(control, 0.79 ± 0.39 pmol/µg protein; relaxin, 1.43 ±
0.50 pmol/µg protein). In the experiments with NS 398, the cells were
pretreated with inhibitor for 1 h and then exposed to other
treatments. At each time point, the medium was collected, and the
IGFBP-1 present in the culture medium was measured using an
enzyme-linked immunosorbent assay (ELISA) kit (Diagnostic Systems Laboratories, Inc. Webster, TX). Cells were lysed with
TriReagent (Molecular Research Center, Inc., Cincinnati,
OH), and RNA was extracted using the protocol provided by the
manufacturer. Cellular protein content was measured using the Micro BCA
protein assay kit (Pierce Chemical Co., Rockford, IL).
PGE2 assay
The PGE2 concentration in cell culture
medium was estimated using a PGE2 enzyme
immunoassay kit from Amersham Pharmacia Biotech (Arlington
Heights, IL). The sensitivity of the assay was 2.5 pg/ml of medium.
Preparation of cell lysates and immunodetection
Stromal cells were grown to confluence on 35-mm (diameter)
dishes and maintained in serum-free medium for 18 h. After each of
the respective treatments, the cells were rinsed twice with ice-cold
PBS, pH 7.4, and lysed on ice with 150 µl lysis buffer, as previously
described (17). Cell lysate proteins (100 µg) were
subjected to 10% SDS-PAGE and were transferred into polyvinylidene
difluoride (PVDF) membranes. The membranes were incubated in PBS
containing 3% BSA and 0.1% Tween 20 for 1 h, followed by
overnight incubation with primary antibody (see legends in Fig. 1
and Fig. 8, A and B, for specific
antibodies). The membranes were rinsed and incubated with the secondary
IgG antibody labeled with horseradish peroxidase for 1 h.
Immunocomplexes were visualized by enhanced chemiluminescence
(Amersham Pharmacia Biotech).
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-smooth-muscle actin (-SMA), IGFBP-1, and
H3.3 (8), were added together in a single tube. The sizes
of the PCR products are as follows: COX-1 (777 bp), COX-2 (449 bp),
-SMA (477 bp), IGFBP-1 (379 bp), H3.3 (213 bp). The PCR products
were electrophoresed in 1.5% agarose gels, and dried gels were
subjected to autoradiography. The resulting film was scanned using a
Phosphoimager (Molecular Dynamics, Inc., Sunnyvale, CA),
and the band intensities were standardized as a ratio of the H3.3
internal standard (8).
Statistical analyses
One-way ANOVA was used to test the null hypothesis of group
differences, followed by a two-tailed Student’s t test for
pairwise comparisons. Each experiment was repeated three times in
triplicate, and a P value of <0.05 was considered
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
In most mammalian cells, IB- serves as a prevalent inhibitor of
NF-B complex (18). Activation of IB-, via
phosphorylation at the Ser32 and
Ser36 residues, results in the release and
nuclear translocation of active NF-B (19). The
immunodetection with phospho-IB- (Ser32)
antibody revealed the presence of activated IB- protein after 5
and 10 min of IL-1ß treatment but not IL-1ra treatment (Fig. 1B).
These data suggest that both p38 MAPK and IB- are phosphorylated
and activated by IL-1ß in baboon stromal cells.
IL-1ß induces COX-2, but not COX-1 gene expression, in stromal
cells
The expression of COX-1 and COX-2 messenger RNA (mRNA), after 1,
4, and 24 h of IL-1ß (10 ng/ml) treatment, was determined by
RT-PCR in baboon stromal fibroblasts (Fig 2). COX-1 mRNA was evident in cells with
no treatment, and no further regulation by IL-1ß was detected during
culture (Fig. 2A). In contrast, after 4 h of IL-1ß stimulation,
there was an increase in COX-2 mRNA, which decreased by 24 h of
incubation (Fig. 2B). Treatment with IL-1 antagonist (IL-1ra, 10
ng/ml), which binds to the IL-1 receptor but does not activate the
signaling pathways, did not induce COX-2 expression. As a positive
control for COX-2 expression, human endometrial epithelial cells (HES)
were treated for 4 h with IL-1ß (13).
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). Addition of IL-ra to IL-1ß resulted
in a decrease in PGE2 production.
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-SMA and IGFBP-1 expression-SMA expression and an increase in IGFBP-1 expression
(see 8, 20). In baboon stromal fibroblasts from
cycling animals, IGFBP-1 expression was evident after incubation with
IL-1ß (10 ng/ml), in the presence of hormones (Fig. 4). When added independently, neither
IL-1ß nor hormones were capable of inducing IGFBP-1 expression in
baboon stromal cells in 3 days. The expression of IGFBP-1 continues to
increase, with time, in culture in the presence of dbcAMP and hormones,
and this is also associated with a decrease in -SMA expression (Fig. 4 and 8). Treatment with IL-1ß and hormones for 6
days also showed a similar response in vitro (Fig 4).
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). After 6 days in culture,
the combination of 0.1 mM dbcAMP and hormones induced the
most amount of IGFBP-1 (2084.4 ± 82.7 pg/µg protein), followed
by IL-1ß in combination with hormones (485.6 ± 206.0 pg/µg
protein) and hormones only (93.1 ± 17.9 pg/µg protein).
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) and a 48%
decrease in human fibroblasts (data not shown). In contrast, the
IGFBP-1 protein induced by dbcAMP and hormones was not affected by
NS-398 (Fig. 6B), confirming that the pathways downstream of COX-2 were
not affected. These results suggest that COX-2-induced
pathway is partially responsible for IL-1ß and hormone-induced
IGFBP-1 expression.
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).
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). In addition, phosphorylation
of IB- was also evident (Fig. 8B). When added together with
hormones, IL-1ß also induces IGFBP-1 protein synthesis (Fig. 8C). In
contrast, in combination with dbcAMP treatment, IL-1ß shows an
inhibitory effect (74%) on IGFBP-1 protein levels similar to that
observed with baboon stromal cells. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-SMA expression in vivo (20) and
in vitro (8). Furthermore, our subsequent
in vivo studies suggested that COX-2 expression in stromal
fibroblasts, underlying the implantation site, precedes IGFBP-1
induction in the decidualized stromal cells (12). Because IL-1ß is expressed both in the progestational endometrium and in trophoblast cells (23, 24), we evaluated IL-1ß as one possible factor that could influence differentiation of stromal cells into decidual cells. IL-1ß has been reported to be actively involved in fetal-maternal interactions (9, 10), but its role in decidualization has not been clarified. In addition, IL-1 can modulate changes in the cytoskeleton (25, 26) and induce COX-2 gene expression (13, 27). Our present data suggest that IL-1ß activates a signaling pathway that induces COX-2 gene expression followed by an increase in IGFBP-1 expression. These data are in agreement with our previous in vivo studies (7, 12). However, there are other reports suggesting that IL-1ß is inhibitory to decidualization (21, 22). In both these studies, the inhibitory effects of IL-1ß on IGFBP-1 and/or PRL synthesis were determined in the presence of dbcAMP or PGE2. Our data are also in agreement with these previously published studies and confirm that IL-1ß in the presence of hormones inhibits dbcAMP-induced IGFBP-1 when all agents are added together.
The up-regulation of IGFBP-1, in response to IL-1ß, is in agreement
with previous in vivo studies in rats and mice (27, 28). Intraperitoneal injections of IL-1 acutely increased serum
levels of IGFBP-1 protein and hepatic IGFBP-1 mRNA synthesis within
2 h of stimulation (29). The direct effects of
cytokines on IGFBP-1 induction were confirmed in vitro using
HepG2 cells (29). IL-1 is a cytokine with many functions
and is capable of inducing multiple immediate signaling pathways in the
cells (reviewed in 30). We detected phosphorylated
IB- protein after 10 min of IL-1ß treatment, suggesting
possible activation of the NFB transcription factor in stromal
fibroblasts. The other cascades activated by IL-1 are those activating
the three best-known types of the MAPK subfamilies, namely p42/p44
extracellular signal-regulated protein kinase, c-Jun
N-terminal kinase, p38 MAPK (31). In our studies we
also detected activation of p38 MAPK kinase after IL-1ß treatment of
baboon and human stromal cells.
IL-1 acts by inducing many genes (e.g. IL-2 and IL-6), chemokines (e.g. IL-8 and monocyte chemotactic protein 1), proteases (e.g. collagenase and stromelysin), adhesion molecules (e.g. intracellular adhesion molecule 1 and E-selectin), and cyclooxygenase (reviewed in 32). In our previous studies, COX-2 expression was detected specifically at the implantation site in baboons (13). In this report, we demonstrate that, in both baboon and human stromal cells cultured in vitro, treatment with IL-1ß induced COX-2 gene expression and PGE2 synthesis. The IL-1ß-induced COX-2 activation contributes to the expression of IGFBP-1, because NS-398, a specific COX-2 inhibitor, partially inhibits the measurable IGFBP-1 protein levels in stromal cells. The lack of complete inhibition indicates that IL-1ß activates at least two immediate signaling pathways leading to IGFBP-1 synthesis in uterine stromal fibroblasts. The alternate pathway may be activated by IL-6. IL-1 has been shown to induce IL-6 production in cultured human decidual cells, and this induction can be prevented by actinomycin treatment (33). IL-6 elevates a 30- to 32-kDa IGF-binding protein in the plasma of mice and increases IGFBP-1 production in HepG2 cells (34). Moreover, specific regions on the IGFBP-1 promoter are regulated by IL-6 (35, 36). Thus, it is conceivable that activation of IL-6 in addition to COX-2 by IL-1ß could account for the lack of complete inhibition of IGFBP-1 expression in the presence of the COX-2 inhibitor. In fact, stimulation with IL-1ß induces IL-6 gene expression in HuF (Strakova, Hales and Fazleabas, unpublished results).
Our current studies have established the signaling pathways activated by IL-1ß in stromal fibroblasts and their role in inducing IGFBP-1 gene expression. The response to IL-1ß has a hormone-independent (COX-2 induction) and hormone-dependent (IGFBP-1 induction) pathway. In the presence of hormones, IL-1ß induces a similar pattern of IGFBP-1 expression and synthesis as that observed with hormones and dbcAMP (8). However, if dbcAMP is present together with IL-1ß, the differentiation process and IGFBP-1 induction are inhibited, suggesting the negative cross-talk between the two pathways. We can only hypothesize how the inhibition is accomplished. The response to IL-1ß or dbcAMP in the presence of hormones, in terms of IGFBP-1 expression, takes 2–3 days. This implies that, after initial stimulus, the decidualization process requires several intermediate steps. IL-1ß-induced PGE2 causes additional cAMP release, because cAMP is a second messenger of PGE2 stimulation (37). The cAMP is known to transmit its signals primarily through PKA, but expression of mRNA of PKA subunits did not differ in nondecidualized and decidualized cells (8). During the course of decidualization, expression of the inducible cAMP early repressor (ICER) is enhanced (38). The ICER is an isoform generated within the cAMP response element (CRE)-binding modulator (CREM) gene, which encodes both activators and repressors of cAMP-induced transcription. Thus, it is conceivable that, in the presence of both dbcAMP and IL-1ß, there is a premature increase in ICER expression that can subsequently inhibit the ability of PGE2-induced cAMP to act positively and enhance IGFBP-1 transcription. Studies to test this hypothesis are currently underway in our laboratory.
Thus, it is evident that cytokines (IL-1) and mediators of cAMP activation (i.e. PGE2) have independent stimulating effects, but synergistic inhibitory effects, in differentiating stromal fibroblasts. The complex signaling pathways activated during implantation may play a critical role in maintaining the appropriate homeostasis required for decidualization and trophoblast invasion.
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Acknowledgments |
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Footnotes |
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Received March 13, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Genes Dev 9:1586–1597 smooth muscle actin expression in the baboon
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