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Reproductive Endocrinology |
Reproductive Endocrinology Center, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California 94143-0556
Address all correspondence and requests for reprints to: Dr. Robert N. Taylor, Reproductive Endocrinology Center, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California 94143-0556.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and interferon-
in endometrial stromal, but not in epithelial or adenocarcinoma cells.
Immunocytochemical studies confirmed the biochemical findings.
Metabolic labeling experiments verified that nascent RANTES secreted by
cytokine-stimulated endometriosis stromal cells was the mature, 8-kDa
protein predicted by the mRNA encoding this chemokine. The results
indicate that RANTES is a normal constituent of the eutopic
endometrium. We propose that secretion of RANTES by ectopic
endometriosis implants provides a mechanism for peritoneal leukocyte
recruitment. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The ip presence of ectopic endometrium per se may have little pathological impact. Recent studies suggest that these implants are sites of local inflammation, and this reaction is responsible for the pain and infertility associated with the clinical disorder (5, 6). Increased numbers of peritoneal macrophages have been found in the pelvic fluid of infertile women with endometriosis (7, 8, 9, 10). In addition, these cells display morphological evidence of activation in endometriosis patients (5, 11, 12). As the chemoattraction of circulating monocytes is regulated by the ß-chemokine RANTES (regulated upon activation, normal T cell expressed and secreted) (13), we postulated that this protein might be secreted into the peritoneal cavity by endometriosis implants. We first tested this hypothesis in a case-control study with peritoneal fluid samples obtained from endometriosis patients and normal controls undergoing laparoscopy. Our findings demonstrated that the pelvic fluid concentrations of RANTES were elevated significantly in women with endometriosis and that these levels correlated with the stage of disease (14). Other monocyte chemoattractant activities (15, 16) also have been found to be increased in pelvic fluid of endometriosis patients, although the correlation with disease stage was variable.
We have undertaken a series of experiments to verify the presence of RANTES messenger ribonucleic acid (mRNA) and localize the expression of RANTES protein in specimens of human endometrium and endometriosis implants and in primary cell cultures isolated from these tissues. Our findings indicate that RANTES is synthesized predominantly in the stromal compartment of normal endometrium and endometriosis tissue. That this chemokine is expressed in both eutopic and ectopic endometrium raises interesting questions about the roles of immunocyte recruitment in normal uterine physiology and in the inflammatory response observed in endometriosis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissue specimens were obtained from patients undergoing
laparoscopy or laparotomy after providing written informed consent
under a study protocol approved by the University of California-San
Francisco committee on human research. Healthy ovulatory women, who had
not received hormones or GnRH agonist therapy for at least 3 months
before surgery, were recruited. Women with endometriosis (mean ±
SD age, 34 ± 5 yr; n = 11) were staged
intraoperatively according to a modification of the revised American
Fertility Society system (17). Control subjects were women with
subserosal leiomyomata or without pelvic pathology requesting tubal
ligation (age, 37 ± 5 yr; n = 11). Endometrial and
endometrioma biopsies were collected under sterile conditions and
transported to the laboratory on ice in MEM with 10% FCS.
Sufficient tissue for RNA, immunohistochemical, and cell culture
analyses was available in about half the cases, so some biopsies were
used only for single studies. All samples and cycle stages were
estimated histologically (18). All normal endometrial biopsies were in
phase and consistent with the patient’s menstrual dating. Biopsies
from endometriosis lesions typically showed flattened epithelium and
compact stroma.
Cell isolation, purification, and culture
Primary endometrial and endometrioma cell cultures were prepared
from biopsies as described previously (19). Biopsy specimens for cell
isolation were obtained from women in the midproliferative phase of the
menstrual cycle. Briefly, the tissue was dissected free from underlying
myometrium or parenchyma, minced into small pieces, digested with
collagenase (2 mg/mL) for 1 h at 37 C, and separated using serial
filtration. Debris was removed by 100-µm aperture sieves, and
epithelial glands were retained on 40-µm aperture sieves and
backwashed onto tissue culture dishes. Stromal cells remaining in the
filtrate were plated onto Primaria (Becton Dickinson, Lincoln Park, NJ)
flasks and allowed to adhere for 30 min, after which blood cells were
removed with phosphate-buffered saline rinses. The cells were cultured
in MEM reconstituted with 10% FCS, nucleosides, essential amino
acids, penicillin G (100 U/mL), streptomycin (100 µg/mL), and
fungizone (1 µg/mL). Exogenous steroids, unless indicated, were not
added to the cultures. Stromal cultures were dissociated with 0.05%
trypsin and 0.02% versene in saline, harvested by centrifugation,
replated, and allowed to grow to confluence. Purification of the
stromal cell population was confirmed by negative staining for the
following antibodies: CD3 (T cells), CD11b (granulocytes), CD45
(monocytes and other leukocytes), and cytokeratin (epithelial cells).
As a control, we used a well differentiated endometrial adenocarcinoma
cell line (Ishikawa cells) obtained from the University of
California-San Francisco Cell Culture Facility.
Cytokine treatment of cell cultures
When the primary cell cultures or Ishikawa cells approached
confluence, the complete medium was removed and replaced with fresh
MEM containing 2.5% FCS and antibiotics, and the cells were
cultured for an additional 48 h. Some wells were treated for
48 h with interferon- (IFN; 100 ng/mL) and tumor necrosis
factor- (TNF; 100 ng/mL; Sigma Chemical Co., St. Louis, MO),
which have been shown to activate RANTES expression in human
endothelial cells (20). Dose-response experiments indicated that this
combination gave a maximal RANTES response in endometrial stromal cells
(Ryan, I. P., and R. N. Taylor, unpublished results).
Extraction and purification of RNA from tissues and cells
Total RNA was extracted from tissues (endometrium, endometrioma, myometrium, and ovary) and from cell cultures (endometrial and endometriosis stromal, epithelial, and Ishikawa cells) using the acid guanidinium isothiocyanate-phenol-chloroform extraction method of Chomczynski and Sacchi (21).
Reverse transcription-PCR (RT-PCR)
Polyadenylated mRNA was preferentially reverse transcribed using
oligo(deoxythymidine) and random hexamer primers. Specific
oligonucleotide primers were designed to amplify sequences from human
RANTES mRNA (193 bp) and human glyceraldehyde-3-phosphate dehydrogenase
(GAPDH; 240 bp) as a positive control (22). The primers used for the
RT-PCR experiments are shown in Table 1
, and those used
to generate complementary RNA (cRNA) probes for the ribonuclease
(RNase) protection assays are shown in Table 2. PCR
cycling was preceded by an initial denaturation at 94 C for 3 min. A
thermal cycle program of 94/57/75 C for 34, 10, and 70 s was run
for seven cycles, followed by a program of 94/66/75 C for 34, 15, and
70 s run for 25 cycles. A terminal extension was run at 75 C for
10 min. The PCR products were separated on 4% agarose gels (3%
NuSieve GTG, 1% SeaKem GTG, FMC Bioproducts, Rockland, ME) and
visualized by ethidium bromide staining (Life Technologies,
Gaithersburg, MD).
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For RNase protection analyses, we generated RANTES and GAPDH
templates by PCR, having engineered T7 RNA polymerase-binding site
sequences 5' to the antisense oligomers for the two gene products (see
Table 2
). RANTES and GAPDH cRNA were labeled with
[-32P]UTP (800 Ci/mmol; Easytides, DuPont, Boston,
MA), synthesized by in vitro transcription using reagents
from the Promega riboprobe system kit (Madison, WI), and gel-purified.
The cRNA probes were hybridized with 10 µg total tissue or cellular
RNA using the Hyb-Speed-RPA-Kit (Ambion, Austin, TX), and the products
were separated on denaturing 8 mol/L urea-5% polyacrylamide gels as
described previously (23). Human placental tissue served as a positive
control for the RNase protection assays and immunostaining studies
described below. Data were analyzed as ratios of the density of RANTES
to GAPDH mRNA signals, determined by computer-assisted densitometry of
the autoradiograms (Scan Analysis, Biosoft, Ferguson, MO).
Immunohistochemistry
Endometrial and endometrioma tissues were fixed for 24 h in 2% paraformaldehyde and 0.5% glutaraldehyde, paraffin-embedded, cut in serial sections of 8 µm, and stained using the Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA). Immunoperoxidase staining was performed overnight at 4 C, using mouse monoclonal IgG antibodies against human cytokeratin 18 (1:2000 dilution; Sigma) and RANTES (0.8 µg/mL; VL2, provided by Drs. Peter Nelson and Alan Krensky, Stanford University, Palo Alto, CA) (24). Controls for the immunostaining specificity included sections stained with anti-RANTES antibodies immunoabsorbed with 10 µg/mL recombinant RANTES protein (R&D Systems, Minneapolis, MN) and sections stained with an identical concentration of an irrelevant mouse monoclonal IgG antibody against human synaptophysin (0.8 µg/mL; Boehringer Mannheim, Mannheim, Germany) that does not stain endometrium. Diaminobenzidine (Zymed, South San Francisco, CA) was used as the chromagen. All sections also were lightly counterstained with hematoxylin.
Immunocytochemistry
Stromal and epithelial cells were plated onto Lab-Tek
four-chamber slides, treated for 48 h in the absence or presence
of IFN (100 ng/mL) and TNF (100 ng/mL), and fixed in 95%
ethanol. Control cultures were stained with May-Gruenwald-Giemsa
reagents. Primary monoclonal antibodies against human vimentin (Sigma),
cytokeratin, RANTES, and synaptophysin were used as described
above.
Immunoprecipitation of metabolically labeled RANTES protein
Cytokine-stimulated endometrial stromal cells were labeled in vitro with [35S]methionine and [35S]cysteine for 48 h. The conditioned medium was collected by centrifugation and concentrated 10-fold by ultrafiltration using a YM3 Amicon membrane (Amicon, Beverly, MA) with a 3-kDa molecular mass cut-off. The concentrated media were precleared with protein A and divided into two parts: one part was treated with VL2 antibody, and the other part was treated with a commercially available monoclonal antibody against RANTES (catalog no. MAB278, R&D Systems). In both cases the same amount of IgG was added (4 µg). The incubation was conducted overnight at 4 C, 50 µL protein A bead slurry (Sigma) were added to the mixture, and the incubation was continued for another hour at 4 C. The protein A beads were collected by centrifugation, and the pellets were washed five times with 50 mmol/L Tris, pH 7.4. The pellets were boiled in 40 µL Laemmli buffer for 3 min and loaded onto a 13.5% polyacrylamide gel.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To verify the expression of RANTES mRNA in endometrial and
endometrioma tissues, we used RT-PCR and RNase protection assays.
RANTES mRNA transcripts were amplified in RNA isolated from normal
endometrium and endometriosis tissues (Fig. 1, upper panel, lanes 2 and 4), but not in myometrium (lane 3)
using RT-PCR. Normal ovarian tissue without evidence of endometriosis
also showed no RANTES transcripts (data not shown). Intron-spanning
primers used to amplify transcripts of a constitutive gene, GAPDH,
indicated that the RNA preparations were of good quality and not
contaminated by genomic DNA (Fig. 1, lower panel, lanes
2–4). Negative controls for reverse transcription and PCR yielded no
nonspecific bands (Fig. 1, lanes 5 and 6).
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, upper panel, lanes 1–4,
respectively) and midproliferative phase endometrioma tissue (Fig. 2, upper panel, lane 6) contained high levels of RANTES mRNA,
whereas myometrium contained scant levels of this transcript (Fig. 2, upper panel, lane 5). RNase protection analyses for GAPDH
mRNA provided a positive control for RNA quantity and integrity (Fig. 2, lower panel, lanes 1–6). These results were
representative of seven independent normal endometrial and four
endometrioma specimens.
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Immunohistochemistry was used to localize RANTES protein in fixed
tissues. A section of normal proliferative endometrium stained with
hematoxylin and eosin is shown in Fig. 3A. An adjacent section, stained with
monoclonal antibodies against cytokeratin, specifically stained the
glandular epithelium (Fig. 3B). Monoclonal IgG antibodies against
RANTES showed the antigen to be localized primarily to the stromal
compartment, with glandular epithelium appearing free of the antigen
(Fig. 3C). Identical concentrations of an irrelevant monoclonal IgG
antibody against synaptophysin served as a negative control (Fig. 3D).
We observed a tendency for some endometrial epithelial cell staining in
the luteal phase of the cycle, but the stroma remained immunopositive
(not shown). Sections of endometrioma stained with cytokeratin (Fig. 3E) and RANTES (Fig. 3F) showed patterns very similar to those observed
in normal endometrium. Note that portions of the ovarian stroma
uninvolved with endometriosis showed very faint to absent RANTES
immunostaining (Fig. 3F). Control experiments were performed on serial
sections of endometrium stained with RANTES antibodies (Fig. 3G) or
the same antibodies immunoabsorbed with excess RANTES protein (Fig. 3H). The latter treatment eliminated the staining pattern and verified
the specificity of the immunolocalization. These results were
representative of eight normal endometrial and four endometrioma
specimens.
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Using an established protocol we isolated and cultured epithelial
and stromal cells from normal endometrium and endometriosis (19). RNase
protection assays were used to quantify RANTES mRNA transcripts in the
two cell types. In the absence of added cytokines, neither stromal nor
epithelial cells isolated from endometriosis or normal endometrial
biopsies were positive for RANTES mRNA (Fig. 4, lanes 4,
6, and 8). However, culturing the cells in the presence of TNF (100
ng/mL) and IFN (100 ng/mL) for 48 h dramatically induced RANTES
mRNA expression in both the ectopic and eutopic endometrial stromal
cells (Fig. 4, lanes 5 and 7), but not in endometrial epithelial cells
(Fig. 4, lane 9). Ishikawa cells, a line derived from a well
differentiated human endometrial epithelial carcinoma (25), also failed
to express RANTES mRNA in the absence or presence of added
cytokines (Fig. 4, lanes 10 and 11, respectively). GAPDH transcripts
were detected in all cells studied and were unaffected by culture in
the presence of cytokines. These results were representative of nine
and eight normal endometrial and endometriosis stromal cell
preparations, respectively, and six and four normal endometrial and
endometriosis epithelial cell preparations, respectively. The Ishikawa
cell findings were confirmed three times.
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Endometrial stromal and epithelial cells were examined
subsequently for RANTES protein expression by immunocytochemistry.
Subconfluent monolayers of endometrial stromal cells were stained with
Giemsa (Fig. 5A), and their
mesenchymal origin was confirmed by positive staining with vimentin
antibodies (Fig. 5B). Stromal cells incubated with RANTES antibodies
showed very faint staining under conditions in which the medium
contained no added cytokines (Fig. 5C). After culturing the cells in
the presence of TNF (100 ng/mL) and IFN (100 ng/mL) for 48 h
(Fig. 5D), an increase in staining intensity was noted to be localized
in nuclei and perinuclear cytoplasm. A 10-kDa intracellular RANTES
precursor is predicted by its complementary DNA sequence (26).
Immunoabsorption with excess RANTES antigen completely eliminated this
staining (Fig. 5E). The addition of estradiol (0.1–10 nmol/L),
medroxyprogesterone acetate (1–100 nmol/L), or a combination of the
two steroids had no effect on the production of immunodetectable
RANTES. These findings were representative of nine stromal cell
preparations.
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), and their epithelial origin was confirmed by
positive immunostaining with cytokeratin antibodies (Fig. 5G). None of
four epithelial cell preparations revealed evidence of RANTES
expression, even after cytokine stimulation (Fig. 5H), corroborating
the absence of RANTES mRNA in cultured normal endometrial epithelial
cells and human endometrial adenocarcinoma cells. Immunoprecipitation of RANTES protein from endometriosis stromal cell supernatants
To verify antibody specificity, we performed immunoprecipitation
analyses of metabolically labeled endometriosis stromal
cell-conditioned medium. These cells were stimulated in
vitro with TNF and IFN for 48 h and were labeled with
[35S]methionine and [35S]cysteine during
this time. The cell supernatants were concentrated and
immunoprecipitated with two monoclonal antibodies (VL2 and the
commercially available MAB278). The autoradiogram shown in Fig. 6 demonstrated that both antibodies immunoprecipitated
an 8-kDa protein band, consistent with the known molecular mass of
secreted human RANTES (26) and identical in size to recombinant human
RANTES protein. Epithelial and unstimulated stromal cells contained no
immunodetectable RANTES.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our findings are of further interest because they demonstrate that stromal cells of normal endometrium also express RANTES mRNA transcripts and protein. The significance of monocyte and T cell recruitment into the normal cycling human endometrium is unknown currently; however, the presence of lymphoid aggregates in the basalis region (28) and the leukocytic infiltration of luteal and early pregnancy decidua (29) have been described. The subtle increase in RANTES gene expression observed in normal endometrium during the ovulatory cycle was less than that noted for endometrial vascular endothelial growth factor mRNA (30). Nevertheless, it is likely that RANTES participates in the normal physiology of the endometrial immunological system.
Some of the contrasting findings of our in vivo and
in vitro studies provide insight into the complexity of
RANTES regulation in the endometrium. RNase protection assays and
immunohistochemical staining of RANTES protein in endometrial and
endometriosis tissues indicate that the chemokine is expressed in the
stroma throughout the ovulatory cycle in vivo. By contrast,
isolated stromal cells cultured in the absence of added cytokines did
not express RANTES mRNA transcripts, and immunocytochemical staining
for RANTES protein was very faint in these cells. However, stimulation
of the cultured stromal cells with IFN and TNF caused a
substantial induction of RANTES mRNA and protein expression. In our
in vitro model, added sex steroids had no apparent effect on
RANTES expression. We documented previously that these stromal cell
cultures were highly purified and were without T cell, macrophage, or
epithelial cell contamination (19). We postulate that endometrial
and endometriosis stromal cells in vivo are exposed to
IFN derived from nearby lymphoid aggregates (31) or resident
leukocytes (6), TNF derived from adjacent endometrial epithelial
cells (32), or other endocrine or paracrine factors capable of inducing
RANTES expression in endometrial and endometriosis tissues.
In the current study only classical, blue-domed endometriosis lesions were examined. Studies are underway to collect biopsies of atypical endometriosis (e.g. flame-like and vesicular) lesions to determine whether these also express RANTES mRNA and protein. A complex network of proinflammatory cytokines and growth-promoting factors appears to be involved in the pathophysiology of endometriosis (14). Some of these proteins may play physiological roles in normal eutopic endometrium. Future clinical strategies aimed at neutralizing potentially pathological factors in the endometriosis syndrome must not lose sight of the possible importance of these molecules in normal endometrial physiology.
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Acknowledgments |
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Footnotes |
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Received November 13, 1996.
Revised January 21, 1997.
Accepted January 31, 1997.
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References |
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plus TNF- and inhibition by
IL-4 and IL-13. J Immunol. 154:1870–1878.[Abstract]
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D. Hornung, K. Klingel, K. Dohrn, R. Kandolf, D. Wallwiener, and R. N. Taylor Regulated on Activation, Normal T-Cell-Expressed and -Secreted mRNA Expression in Normal Endometrium and Endometriotic Implants : Assessment of Autocrine/Paracrine Regulation by in Situ Hybridization Am. J. Pathol., June 1, 2001; 158(6): 1949 - 1954. [Abstract] [Full Text] [PDF]
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 P. M. Drake, M. D. Gunn, I. F. Charo, C.-L. Tsou, Y. Zhou, L. Huang, and S. J. Fisher Human Placental Cytotrophoblasts Attract Monocytes and Cd56bright Natural Killer Cells via the Actions of Monocyte Inflammatory Protein 1{alpha} J. Exp. Med., May 21, 2001; 193(10): 1199 - 1212. [Abstract] [Full Text] [PDF]
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T. Sugano, H. Narahara, K. Nasu, K. Arima, K. Fujisawa, and I. Miyakawa Effects of platelet-activating factor on cytokine production by human uterine cervical fibroblasts Mol. Hum. Reprod., May 1, 2001; 7(5): 475 - 481. [Abstract] [Full Text] [PDF]
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D. Hornung, F. Bentzien, D. Wallwiener, L. Kiesel, and R.N. Taylor Chemokine bioactivity of RANTES in endometriotic and normal endometrial stromal cells and peritoneal fluid Mol. Hum. Reprod., February 1, 2001; 7(2): 163 - 168. [Abstract] [Full Text] [PDF]
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D. Hornung, K. Dohrn, K. Sotlar, R. R. Greb, D. Wallwiener, L. Kiesel, and R. N. Taylor Localization in Tissues and Secretion of Eotaxin by Cells from Normal Endometrium and Endometriosis J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2604 - 2608. [Abstract] [Full Text]
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A. Boucher, W. Mourad, J. Mailloux, A. Lemay, and A. Akoum Ovarian hormones modulate monocyte chemotactic protein-1 expression in endometrial cells of women with endometriosis Mol. Hum. Reprod., July 1, 2000; 6(7): 618 - 626. [Abstract] [Full Text] [PDF]
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R. D. Blumenthal, M. Samoszuk, A. P. Taylor, G. Brown, R. Alisauskas, and D. M. Goldenberg Degranulating Eosinophils in Human Endometriosis Am. J. Pathol., May 1, 2000; 156(5): 1581 - 1588. [Abstract] [Full Text] [PDF]
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K. Arima, K. Nasu, H. Narahara, K. Fujisawa, N. Matsui, and I. Miyakawa Effects of lipopolysaccharide and cytokines on production of RANTES by cultured human endometrial stromal cells Mol. Hum. Reprod., March 1, 2000; 6(3): 246 - 251. [Abstract] [Full Text] [PDF]
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D. I. Lebovic, F. Bentzien, V. A. Chao, E. N. Garrett, Y.G. Meng, and R. N. Taylor Induction of an angiogenic phenotype in endometriotic stromal cell cultures by interleukin-1{beta} Mol. Hum. Reprod., March 1, 2000; 6(3): 269 - 275. [Abstract] [Full Text] [PDF]
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A. Akoum, C. Jolicoeur, and A. Boucher Estradiol Amplifies Interleukin-1-Induced Monocyte Chemotactic Protein-1 Expression by Ectopic Endometrial Cells of Women with Endometriosis J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 896 - 904. [Abstract] [Full Text]
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J. Zhang, L. J. Lathbury, and L. A. Salamonsen Expression of the Chemokine Eotaxin and Its Receptor, CCR3, in Human Endometrium Biol Reprod, February 1, 2000; 62(2): 404 - 411. [Abstract] [Full Text]
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A. Arici, L. M. Senturk, E. Seli, M. O. Bahtiyar, and G. Kim Regulation of Monocyte Chemotactic Protein-1 Expression in Human Endometrial Stromal Cells by Estrogen and Progesterone Biol Reprod, July 1, 1999; 61(1): 85 - 90. [Abstract] [Full Text]
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A.J. Vincent, N. Malakooti, J. Zhang, P.A.W. Rogers, B. Affandi, and L.A. Salamonsen Endometrial breakdown in women using Norplant is associated with migratory cells expressing matrix metalloproteinase-9 (gelatinase B) Hum. Reprod., March 1, 1999; 14(3): 807 - 815. [Abstract] [Full Text] [PDF]
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O. Ayad, J. M. Stark, M. M. Fiedler, I. Y. Menendez, M. A. Ryan, and H. R. Wong The Heat Shock Response Inhibits RANTES Gene Expression in Cultured Human Lung Epithelium J. Immunol., September 1, 1998; 161(5): 2594 - 2599. [Abstract] [Full Text] [PDF]
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