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Original Studies |
Medical Research Council Reproductive Biology Unit (H.N.J., S.C.B.) and the Department of Obstetrics and Gynecology (H.O.D.C.), Center for Reproductive Biology, Edinburgh, United Kingdom EH3 9EW
Address all correspondence and requests for reprints to: Dr. H. N. Jabbour, Medical Research Council Reproductive Biology Unit, Center for Reproductive Biology, 37 Chalmers Street, Edinburgh, United Kingdom EH3 9EW. E-mail: h.jabbour{at}ed-rbu.mrc.ac.uk
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Introduction |
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The precise role and mechanism of action of PRL in pregnant and nonpregnant endometrium have not been clarified. The temporal pattern of expression of both PRL and its receptor in the human endometrium suggest a pivotal role for the hormone during pregnancy. PRL receptors have been localized to the decidua, chorionic cytotrophoblast, placental trophoblast, and amniotic epithelium (11). Moreover, PRL receptor expression has been localized by immunohistochemistry to the stromal and glandular compartments of the endometrium during the menstrual cycle (12). This observation outlined a possible role for PRL in preparation of the endometrium for implantation of the trophoblast. A critical role for PRL in the process of implantation and successful establishment of pregnancy was ascertained recently after "knockout" of the PRL receptor gene. Female mice with a homozygous null mutation of the PRL receptor are sterile, and their uteri are refractory to implantation (13). PRL may influence the process of implantation through modification of the immune environment of the endometrium at the time of implantation (14, 15) and/or by regulation of the expression of a factor(s) within the glandular secretions that may control trophoblast proliferation and/or invasion of the endometrium.
The following study was designed to investigate further the pattern of expression of the PRL receptor gene in nonpregnant human endometrium. In addition, PRL intracellular signaling in nonpregnant endometrium was assessed by investigating the phosphorylation of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins after short term culture of human endometrium with PRL. Tyrosine phosphorylation of the JAK/STAT proteins after interaction of PRL with its receptor is part of the signaling pathway for transcription of PRL-responsive genes that are involved in mediating both proliferative and differentiative effects of PRL (15, 16).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Normal endometrial tissue was collected with a pipelle suction curette (Pipelle, Laboratoire CCD, Paris, France) from fertile women with regular menstrual cycles (25–35 days) who were undergoing minor gynecological procedures. Subjects had not been exposed to exogenous hormones for at least 6 months before inclusion in the study. Written informed consent was received before tissue collection, and ethical approval was received from the Lothian Research ethics committee. Tissue collected for in situ hybridization (proliferative phase endometrium, n = 3; secretory phase endometrium, n = 3) was snap-frozen in isopentane precooled with dry ice and subsequently stored at -70 C. Tissue collected for immunohistochemistry (proliferative phase endometrium, n = 4; secretory phase endometrium, n = 4) was fixed by immersion in 10% neutral buffered saline overnight at 4 C before routine paraffin embedding. Tissue collected for the ribonuclease (RNase) protection assay (RPA; secretory phase endometrium, n = 5) was snap-frozen in dry ice and stored at -70 C. Tissue used for in vitro culture (secretory phase endometrium, n = 7) was promptly immersed in RPMI 1640 medium (Sigma Chemical Co., Dorset, UK) containing 2 mmol/L L-glutamine, 100 U/mL penicillin, and 100 µg/mL streptomycin and transported to the culture facility.
In situ hybridization
Cryostat tissue sections (5 µm) were thaw-mounted onto
3-aminopropyltriethoxy silane (TESPA)-coated and baked slides (2%
TESPA in acetone; Sigma) and fixed for 5 min in 4% (wt/vol)
paraformaldehyde made up in 0.1 mol/L phosphate-buffered saline. The
slides were acetylated and prehybridized for 2 h at 55 C in
prehybridization buffer consisting of 50% deionized formamide, 5
x SSPE [single x SSPE contains 0.15 mol/L NaCl, 10 mmol/L
NaH2PO4·H2O, and 1 mmol/L
ethylenediamine tetraacetate (EDTA)], 5 x Denhardt’s solution,
200 µg/mL yeast transfer ribonucleic acid (RNA), 200 µg/mL
denatured salmon sperm DNA, and 1% SDS. Hybridization was then
performed overnight in hybridization buffer (prehybridization buffer
plus 4% dextran sulfate and 10 mmol/L dithiothreitol) containing
1 x 106 cpm [
-33P]UTP-labeled
complementary RNA (cRNA). Excess probe was removed by washing in 4
x SSC (single x SSC contains 0.15 mol/L NaCl and 15 mmol/L
sodium citrate, pH 7) at room temperature before the sections were
treated with RNase A (20 µg/mL). The sections were subsequently
incubated with 4 x SSC, 2 x SSC, and 0.1 x SSC for 30
min each at room temperature. Tissues were dehydrated progressively in
alcohol (50%, 85%, and 95%) containing 0.3 mol/L ammonium acetate
and air-dried before being dipped in NTB-2 emulsion (Eastman Kodak,
Cambridge, UK). After incubation in a humidified box overnight, tissues
were placed in a sealed dark box at 4 C for 3 weeks, developed with D19
developer, and fixed with Unifix (Kodak) at 14 C in the dark room.
Labeled sense and antisense cRNA were synthesized by incubation of
linearized template [1 µg; pGEM containing a 645 bp complementary
DNA (cDNA) fragment previously generated by PCR (12) between bp 154 and
798 of the human PRL receptor sequence (16)] with 50 µCi
[-33P]UTP (2000 Ci/mmol; Amersham, Aylesbury, UK) in
the presence of T7 or SP6 RNA polymerase for 30 min at 37 C according
to the manufacturer’s recommendations (Promega, Southhampton, UK).
Histology and immunocytochemistry
Five-micron paraffin wax-embedded sections were cut and mounted
on slides coated with 2% TESPA in acetone. Slides were then dried
overnight at 50 C before dewaxing in Histoclear (National Diagnostics,
Hull, UK). Tissues were rehydrated in graded ethanol and washed in
water followed by TBS (0.05 mol/L Tris-HCl, pH 7.4, and 0.85% NaCl).
Sections were treated with 10% hydrogen peroxide in methanol for 30
min and then blocked for 30 min with normal swine serum (NSS) diluted
1:5 in TBS and 5% BSA. The primary antibodies used were PRL receptor
raised in rabbit against a peptide sequence from the extracellular
domain of the rat PRL receptor (1:50 dilution; donated by Dr. P.
M. Ingleton, University of Sheffield, Sheffield, UK) (17), rabbit
anti-human PRL (1:100 dilution; Dako, High Wycombe, Buckinghamshire,
UK), rabbit anti-mouse JAK2 (1:200 dilution; the JAK2 antibody is
raised against a peptide sequence corresponding to amino acids 758–776
and is non cross-reactive with JAK1, JAK3, and Tyk2; supplied by
Autogenbioclear, Wiltshire, Calne, UK), rabbit antihuman STAT1 (1:50
dilution; the STAT1 antibody is raised against a peptide sequence
corresponding to amino acids 688–710 mapping within a
carboxyl-terminal sequence common to STAT1ß p84 and STAT1 p91 and
is noncross-reactive with STAT2 p113, STAT3, STAT4, STAT5, and STAT6;
supplied by Autogenbioclear), and mouse antihuman STAT5 (1:50 dilution;
the STAT5 antibody is raised against a peptide sequence corresponding
to amino acids 759–775 mapping at the carboxyl-terminus of STAT5b and
is noncross-reactive with STAT1ß p84, STAT2p113, STAT3, STAT4, and
STAT6; supplied by Autogenbioclear). The polyclonal antibody was
diluted in NSS-TBS and 5% BSA (see above) and incubated on the
sections overnight at 4 C under plastic coverslips. Control sections
were incubated with nonimmune rabbit or mouse serum. After removal of
coverslips, sections were washed twice in TBS (5 min each), incubated
for 30 min with biotinylated swine antirabbit or goat antimouse IgG
(Dako) diluted 1:500 in NSS-TBS, then washed again twice in TBS (5 min
each) and incubated with peroxidase-antiperoxidase conjugated to
avidin-biotin complex (Dako) for 30 min at room temperature. Color
reaction was developed by incubation in a mixture of 0.05%
3,3'-diaminobenzidine (Sigma) in 10 mL 0.05 mol/L Tris-HCl buffer (pH
7.4) and 0.033% hydrogen peroxide.
RNA extraction and RNase protection assay
RNA was extracted from secretory phase endometrium using
Tri-Reagent as recommended by the manufacturer (Sigma). RNA yields were
estimated by spectrophotometry at 260 nm. For the RPA, an antisense
cRNA was prepared from SphI-linearized pGEM plasmid
containing the 645-bp cDNA fragment of the human PRL receptor described
above. The RPA was conducted using the Ambion RPA II kit (AMS
Biotechnology Europe, Oxfordshire, UK) as instructed by the
manufacturer. Briefly, the linearized plasmid was incubated with SP6
RNA polymerase for 30 min in the presence of [-32P]UTP
(800 Ci/mmol; Amersham) mixed with loading dye (95% formamide, 0.025%
bromophenol blue, 0.025% xylene cyanol, 30% glycerol, 0.5 mmol/L
EDTA, and 0.025% SDS), heated at 95 C for 3 min, and separated on a
denaturing 5% (wt/vol) acrylamide gel for 3 h at 50 watts. The
gel was then covered in Saran wrap and exposed for 2 min to XAR-5 film
(Kodak) to determine the location of the full-length radiolabeled cRNA.
The appropriate portion of the gel was cut out, placed in an Eppendorf
tube together with 350 µL elution buffer [containing 0.5 mol/L
ammonium acetate, 1 mmol/L EDTA, and 0.2% (wt/vol) SDS], and
incubated overnight at 37 C. The activity of 2 x 1 µL aliquots
was determined by liquid scintillation spectroscopy. The average of the
samples was determined, and the volume of radiolabeled probe required
to give 2 x 105 cpm was calculated. Total RNA (50
µg) from secretory phase endometrium (n = 5) and yeast (n =
2; used as reaction controls in the presence or absence of RNase
digestion to establish the specificity of the hybridization reaction
and the size of the unprotected RNA fragment) was mixed with the
radiolabeled probe and hybridization buffer, heated to 90 C for 4 min,
and incubated overnight at 45 C. The integrity of the RNA and the
relative amount of total RNA in each reaction were determined by
including radiolabeled cRNA prepared from an 18S ribosomal standard
cDNA in each reaction. The next day, single stranded RNA were digested
using 250 U/mL RNase A and 10,000 U/mL RNase T1 at 37 C for 30 min. The
protected RNA was precipitated and resuspended in gel loading buffer
(95% formamide, 0.025% xylene cyanol, 0.025% bromophenol blue, 0.5
mmol/L EDTA, and 0.025% SDS), heated at 95 C for 3 min, and separated
on a 5% acrylamide gel under denaturing conditions. The gel was dried
under vacuum and initially exposed to a phosphorescent screen
(Molecular Dynamic, UK) followed by exposure to an autoradiographic
film (XAR-5, Kodak, Chesham).
In vitro culture and Western blotting
The tissue was washed in PBS (prewarmed to 37 C) twice and subsequently minced thoroughly with fine scissors. Two sets of experiments were conducted. Exp A was designed to investigate the time course of phosphorylation of JAK/STAT proteins in the endometrium, and Exp B was designed to investigate the differential phosphorylation of JAK/STAT proteins in the stromal and glandular compartments of endometrium. For Exp A, each sample (n = 3 samples of secretory phase endometrium) was separated into five equal aliquots. One aliquot was snap-frozen in dry ice at the beginning of the experiment and used as a control. The other four aliquots were cultured in 2 mL RPMI 1640 medium (containing 2 mmol/L L-glutamine, 100 U/mL penicillin, and 100 µg/mL streptomycin) and 100 ng/mL human PRL (hPRL-SIAFP-B2, donated by NIDDK, NIH). The tissue was incubated in a 37 C incubator with 5% CO2 for 5, 10, 15, and 20 min after the addition of human PRL. Subsequently, the tissue was snap-frozen in dry ice and stored at -20 C.
For Exp B, each sample (n = 4 samples of secretory phase endometrium; two samples for JAK2 phosphorylation and two samples for STAT1 and STAT5 phosphorylation) was digested with 1 mg/mL collagenase and 0.1 mg/mL deoxyribonuclease for approximately 45 min at 37 C. The digested tissue was filtered through 200- and 40-µm pore size filters to separate the stromal and glandular compartments of the endometrium. Cells from the stromal and glandular compartments were divided into two aliquots and incubated in RPMI 1640 medium (containing 2 mmol/L L-glutamine, 100 U/mL penicillin, and 100 µg/mL streptomycin) with 0 or 100 ng/mL human PRL. The cells were cultured for either 5 min (for JAK2 phosphorylation) or 20 min (for STAT1 and STAT5 phosphorylation). Subsequently, the cells were snap-frozen in dry ice and stored at -20 C.
After culture, the cells were lysed in 500 µL lysis buffer [60 mmol/L Tris-HCl (pH 6.8), 1 mmol/L sodium vanadate, 10% glycerol, and 2% SDS] containing protease inhibitors (44 µg/mL aprotinin and 1 mmol/L phenylmethylsulfonylfluoride). The insoluble material was discarded by centrifugation, and 100 µg lysate protein were incubated with mouse monoclonal antiphosphotyrosine antibody (5 µg/mL; Affiniti, Exeter, UK) overnight at 4 C. The precipitated phosphorylated proteins were separated by incubation with Dynabeads M-450 rat antimouse IgG2b (Dynal, Wirral, UK). The complexes were extensively washed in PBS and boiled for 5 min in sample buffer [125 mmol/L Tris-HCl (pH 6.8), 4% SDS, 2.5% dithiothreitol, 20% glycerol, and 0.05% bromophenol blue], and the beads were separated from the precipitated proteins by a Dynal MPC magnet. The precipitated proteins were loaded on a 7.5% polyacrylamide gel, transferred to a polyvinylidene difluoride membrane (Millipore, Watford, UK), and subjected to immunoblot analysis with JAK2 (1:200), STAT1 (1:100), and STAT5 (1:500) antibodies for 2 h at room temperature. Subsequently, the membranes were incubated with an antirabbit or antimouse IgG conjugated to horseradish peroxidase (1:2000) for 1 h at room temperature before being washed three times for 15 min each time in washing buffer [50 mmol/L Tris-HCl, 150 mmol/L NaCl, and 0.05% (vol/vol) Tween-20], and labeled bands were revealed by chemiluminescence (ECL kit, Amersham). In Exp A, each blot (total of three) was probed with the JAK2, STAT1, and STAT5 antibodies. Probing of the blots with STAT6 antibody (1:500; the STAT6 antibody was raised against a peptide sequence corresponding to amino acids 828–847; supplied by Autogenbioclear) was conducted as a negative control to confirm the specificity of phosphorylation of the STAT1/STAT5 antibodies in response to stimulation with PRL.
In Exp B, each blot (total of two) prepared from tissue incubated with or without PRL for 20 min was probed with STAT1 and STAT5 antibodies (the blots incubated with or without PRL for 5 min were probed with JAK2 only). For reprobing, the blots were stripped by incubation in stripping buffer [62.5 mmol/L Tris (pH 6.8), 3% SDS, and 50 mmol/L dithiothreitol] twice at 55 C for 30 min each time followed by three washes in TBS-Tween [50 mmol/L Tris-HCl, 150 mmol/L NaCl, and 0.05% (vol/vol) Tween-20].
Successful separation of the stromal from glandular compartments in Exp
B was confirmed by Western blotting of proteins extracted form the two
compartments with a rabbit antihuman PRL antibody (1:75 dilution; Dako)
as a stromal cell marker and a mouse monoclonal cytokeratin 18 antibody
(1:100 dilution; Autogenbioclear) as a glandular epithelial cell
marker. PRL immunoreactivity was evident only in the stromal
compartment, whereas cytokeratin immunoreactivity was evident only in
the glandular compartment (Fig. 1
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and was up-regulated during the
secretory phase (Fig. 2B) of the menstrual cycle, and the site of
expression was localized to the stromal compartment of the endometrium.
In situ hybridization confirmed expression of the PRL
receptor gene in the human endometrium. Negligible signal was detected
in samples collected during the proliferative phase (data not shown).
In secretory phase endometrium, PRL receptor expression was apparent
and localized to the stromal and glandular compartments (Fig. 2, D and
E). A similar pattern of expression was detected by
immunohistochemistry using a PRL receptor antibody. Expression of the
receptor was detected during the secretory phase of the menstrual cycle
and was localized to endometrial glands and a subset of stromal cells
(Fig. 2, G and H). In addition, positive staining was observed in a
population of hematopoietic cells within the endometrium
(inset of Fig. 2H). PRL receptor expression in the human
endometrium during the secretory phase was confirmed further by RPA
(Fig. 3). All five samples collected
between days 19–21 of the menstrual cycle demonstrated expression of
the PRL receptor.
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). Similarly, STAT1 and STAT5, but not
STAT6 (data not shown), phosphorylation was observed after stimulation
with PRL. Reactive bands of approximately 84/91 kDa corresponding to
the two variant forms of STAT1 (Fig. 4B) and of 94 kDa corresponding to
STAT5 (Fig. 4C) were detected within 20 min after stimulation with
PRL.
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, A and B) and
STAT5 (Fig. 5, G and H) displayed a similar temporal pattern of
expression. JAK2 and STAT5 immunoreactivity was observed during the
secretory phase and was negligible during the proliferative phase of
the menstrual cycle. However, immunoreactivity with the STAT1 antibody
was detected during both the proliferative and secretory phases of the
menstrual cycle (Fig. 5, D and E).
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). By contrast, phosphorylation of the
STAT1 and STAT5 proteins was more apparent in the endometrial glands
than in the stromal tissue after stimulation with PRL (Fig. 6, B and
C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PRL, through its membrane-bound receptor, is known to regulate the growth and differentiation of a wide variety of cells. The pattern of expression of the PRL receptor gene in glandular epithelial cells suggests that endometrial PRL is mediating a differentiative, rather than a mitogenic, effect in the glandular compartment. This is inferred from the absence of expression of the receptor during the proliferative phase of the menstrual cycle, the period during which the glandular epithelial cells are undergoing rapid mitogenesis. The abundant expression of the receptor during the secretory phase implies that PRL may be regulating the secretory function of the endometrial glands. Whether PRL-modulated factors within the endometrial glands influence trophoblast function and subsequent establishment of pregnancy remains to be established. Expression of the PRL receptor has also been demonstrated in cells of hematopoietic origin within the stromal compartment of the endometrium. In recent years, a role for PRL in immunomodulation has been emphasized (28, 29). Hypophysectomy or bromocriptine treatment suppresses the growth of the thymus (30), T cell proliferation (31), and production of cytokines (32). In addition, PRL and PRL receptor expression have been described in a number of hematopoietic cells in the peripheral circulation, such as lymphocytes and mononuclear cells (14, 33), suggesting that PRL acts in an autocrine/paracrine fashion to influence immune cell proliferation and function. The demonstration of expression of PRL receptors in hematopoietic cells within the endometrium is not surprising because these cells are likely to be recruited from the peripheral circulation (34). However, these cells may undergo in situ proliferation and differentiation. Endometrial hematopoietic cells increase in number during the secretory phase of the menstrual cycle (35) and have different phenotypic characteristics from those of hematopoietic cells within the peripheral circulation (36, 37). Hematopoietic cell proliferation and differentiation during the secretory phase of the menstrual cycle and early pregnancy may play a vital role in the control of implantation and establishment of vasculature and blood supply at the fetoplacental unit (15). The local signal(s) responsible for these uterine immune cell modifications may be orchestrated by PRL, which is expressed at increasing concentrations by the pseudodecidualized and decidualized endometrium during the secretory phase of the menstrual cycle and early pregnancy.
PRL has been demonstrated previously to activate JAK2 and different
STAT proteins, including STAT1 and STAT5 (reviewed in Ref. 38). The
activated STAT proteins are translocated into the nucleus and
subsequently up-regulate the transcription of target promoters, such as
ß-casein (39), ß-lactoglobulin (40), whey acidic protein (41),
2-macroglobulin (42), and Interferon Regulatory Factor-1
(43), which mediate differentiative or mitogenic effects of PRL. The
data presented in this study provide evidence that the PRL receptors
expressed in the human endometrium may use the JAK/STAT signaling
pathway in vivo. In vivo phosphorylation of
JAK/STAT proteins after stimulation with PRL has been reported recently
in the rat ovaries (44) and mammary gland (45). The
immunohistochemistry and Western blotting data have demonstrated the
colocalization of the PRL receptors with the JAK and STAT proteins and
the activation/phosphorylation of JAK/STAT proteins in response to
stimulation with PRL at least in the glandular compartment. The
temporal pattern of phosphorylation of the JAK/STAT proteins confirms
that upon ligand binding, JAK2 is rapidly phosphorylated and is
followed by phosphorylation of the different STAT proteins. A similar
pathway may be operating in stromal cells, although this was not as
apparent in the present study. This may be a reflection of the lower
level of expression of PRL receptors in the stromal tissue compared
with the endometrial glands. The target genes for PRL function in the
endometrial glands remain to be established, although it is evident
that the putative PRL-inducible genes are regulated in part by the
STAT1 and STAT5 proteins. The function of the different STAT proteins
in signal transduction may vary with the different target genes
investigated. Comparative studies have demonstrated that STAT1 and
STAT5 proteins can act as both positive and negative regulators of gene
transcription (46). For example, STAT5 is a positive regulator of
PRL-induced transcription of the ß-casein promoter (46) and the
2-macroglobulin promoters (47), whereas PRL-induced
transcription of the Interferon Regulatory Factor-1 promoter is
inhibited by STAT5 and promoted by STAT1 (46).
In conclusion, this study has demonstrated expression of functional PRL receptors in the nonpregnant human endometrium during the secretory phase of the menstrual cycle. PRL induces gene transcription in the endometrium through the JAK/STAT pathway. The temporal pattern and site of expression of the receptor in the endometrium suggest that PRL may mediate an array of functions that are linked to the described mitogenic and differentiative effects of the hormone on target tissue.
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Acknowledgments |
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Received November 6, 1997.
Revised March 16, 1998.
Accepted April 16, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2-macroglobulin (2M) promoter:
relation to the expression of 2M in the rat ovary. Biol Reprod. 55:1029–1038.[Abstract]
2 macroglobulin
gene in rat ovarian granulosa cells: Stat 5 activation and binding to
the interleukin-6 response element. Mol Endocrinol. 10:171–184.[Abstract]
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