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Original Studies |
Departments of Obstetrics and Gynecology and Pathology (L.S.G.), Yale University School of Medicine, New Haven, Connecticut 06520
Address all correspondence and requests for reprints to: Aydin Arici, M.D., Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8063. E-mail: aydin.arici{at}yale.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The endometrium is involved in multiple unique functions. This tissue is responsive to sex steroid hormones, undergoes extraordinary growth in a cyclic manner, and is shed and regenerated nearly 450 times in the lifetime of women. Endometrium/decidua is capable of blastocyst implantation, immunological tolerance, regulation of trophoblast invasion, infectious agent control, and efficient disposal of blood and desquamated cellular debris with menstruation. To accomplish these many diverse functions, it seems reasonable to suspect that multiple mechanisms must be operative to recruit and to engage the functions of various leukocytes in a timely and specific manner. The validity of this deduction is supported by the large number of leukocytes of various types that normally are present in a predictable pattern in endometrial/decidual tissues. Much experimentation has been conducted to characterize and evaluate the function of leukocytes in endometrium and to define the contributions of these cells to reproductive function. For example, large numbers of neutrophils infiltrate the endometrium immediately before the onset of menstruation, and the number of uterine large granular lymphocytes increases strikingly in the endometrium after ovulation at the expected time of implantation and during early placentation (2).
One of the factors thought to play a role in the recruitment of
leukocytes to endometrium is interleukin-8 (IL-8), a cytokine with
neutrophil chemotactic/activating and T cell chemotactic activity both
in vivo and in vitro (3, 4). It is synthesized as
a 99-amino acid precursor and secreted as a 72-amino acid peptide after
successive removal of amino-terminal residues. Its known actions
include chemotaxis and activation of neutrophils, expression of surface
adhesion molecules on neutrophils, angiogenesis (chemotaxis of
endothelial cells) (5), and mitogenesis of epidermal (6), melanoma (7),
and vascular smooth muscle cells (8). IL-8 is produced by a number of
cell types, including peripheral blood monocytes (9), endothelial cells
(10), fibroblasts (11), neutrophils (12), keratinocytes (11), synovial
cells (13), and cells derived from human decidua and chorion laeve
tissues (14). We have previously shown that IL-8 is produced by
endometrial stromal and epithelial cells in culture and that this
production is regulated by IL-1
and tumor necrosis factor-
(TNF) (15). We and others have also shown that IL-8 levels are
increased in the peritoneal fluid of women with endometriosis compared
to those in healthy women (16, 17).
In the present study, we investigated menstrual cycle-dependent expression of IL-8 messenger ribonucleic acid (mRNA) and protein in the human endometrium.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Endometrial tissue (n = 55) was obtained from women who underwent hysterectomy conducted for reasons other than endometrial disease or from endometrial biopsies. Written informed consent was obtained from each woman before surgery, using consent forms and protocols approved by the human investigation committee of Yale University. The day of the menstrual cycle was established from the woman’s menstrual history and was confirmed by histology.
Northern analysis
The tissues used for RNA extraction (n = 26) were frozen in liquid nitrogen and stored at -80 C before isolation of RNA. Total RNA was prepared by the guanidium isothiocyanate-cesium chloride ultracentrifugation method of Chirgwin et al. (18). Total RNA was size-fractionated by electrophoresis on 1% formaldehyde-agarose gels, transferred electrophoretically to Hybond-N+ membrane (Amersham, Arlington Heights, IL), and cross-linked to the membrane by the use of UV light.
The sequence of the proximal 3'-untranslated region of the human
IL-8 complementary DNA was obtained from GenBank (accession no.
Y00787). Two complementary oligonucleotides were synthesized by the
Keck Biotechnology Resource Laboratory at Yale University. The strands
were annealed to give double-stranded DNA. A 70-bp region was cloned
into pGEM plasmid. Plasmids containing the sequence from the
3'-untranslated regions of IL-8 were used for transformation. Plasmid
DNA was isolated by alkaline lysis method, purified over Qiagen columns
(Qiagen, Chatsworth, CA), and linearized with EcoRI or
HindIII. Linearized plasmid DNA was ethanol precipitated and
used as template for generation of riboprobes. Radiolabeled RNA probes
were generated by in vitro transcription. Sense and
antisense probes were generated with the appropriately digested
template and the corresponding RNA polymerase (T7 or SP6) and labeled
with [-32P]UTP. Hybridization was performed overnight
at 60 C in buffer comprised of formamide (50%, vol/vol), 1 x
standard saline citrate (SSC), 5 x Denhardt’s buffer, transfer
RNA (0.2%, wt/vol), and 32P-labeled riboprobe (2 x
106 cpm/mL). The membrane was washed twice at 68 C for 30
min each time in 0.1 x SSC-SDS (0.1%, wt/vol). Kodak X-Omat AR
film (Eastman Kodak, Rochester, NY) was exposed overnight at -70
C.
The autoradiographic bands were quantified by using a laser densitometer (Molecular Dynamics, Sunnyvale, CA). Each IL-8 band was normalized using the value for the corresponding glyceraldehyde-3-phosphate dehydrogenase, thus correcting for any variation in the amount of mRNA applied to each lane.
Immunohistochemistry
Endometrial tissue samples (n = 26) were obtained and snap-frozen in OCT (Tissue Tek, Sakura, Torrance, CA). Serial 6- to 8-µm cryosections were placed on poly-L-lysine-coated glass microscope slides and fixed in acetone for 10 min at 4 C. Sections were rinsed twice in phosphate-buffered saline (PBS; pH: 7.4) for 5 min each time and in PBS with 0.1% BSA (PBS-BSA; 0.1%, wt/vol) for 5 min. Slides were then incubated with 2% blocking horse serum (Vector Laboratories, Burlingame, CA) for 1 h at room temperature in a humidified chamber. Excess serum was drained, and primary antibody (murine monoclonal antihuman IL-8, clone: Nap II, IgG1; 10 µg/mL; Bender Med Systems, Vienna, Austria) in PBS-BSA 0.1% was directly added to the sections and incubated overnight at 4 C in a humidified chamber. The specificity of this antibody was validated by incubation with an excess amount of recombinant IL-8 that eliminated the staining. For a negative control, nonspecific mouse IgG was used at same concentration. Endogenous peroxidase activity was quenched with 0.6% H2O2 in PBS (vol/vol) for 15 min. Sections were rinsed, then biotinylated horse antimouse antibody (1.5 mg/mL; Vector Laboratories) was added at a 1:200 dilution for 45 min at room temperature. The antigen-antibody complex was detected using an avidin-biotin-peroxidase kit (ABC, Vector Laboratories). Diaminobenzidine (3,3-diaminobenzidine tetrahydrochloride dihydrate, Aldrich Chemical Co., Milwaukee, WI)-hydrogen peroxide (0.5 mg in 0.03% H2O2 in PBS) was used as the chromogen, and sections were counterstained with hematoxylin, then mounted with Permount (Fisher Chemicals, Springfield, NJ).
Immunohistochemistry staining was scored in a semiquantitative fashion,
incorporating both the intensity and the distribution of specific
staining (19). The evaluations were recorded as percentages of
positively stained target cells in each of four intensity categories,
which were denoted as 0 (no staining), 1+ (weak but detectable above
control), 2+ (distinct), and 3+ (intense). For each tissue, an HSCORE
value was derived by summing the percentages of cells staining at each
intensity multiplied by the weighted intensity of the staining
[HSCORE = 
Pi (i + 1), where i is the intensity
scores, and Pi is the corresponding percentage of the
cells].
Statistical analysis
Because the levels of IL-8 mRNA and immunohistochemistry scores in the endometrium were not normally distributed, they were analyzed with nonparametric NAOVA by ranks (Kruskal-Wallis test). Statistical calculations were performed using Statistical Package for Social Sciences version 6.0 for Windows (SPSS, Chicago, IL).
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Results |
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Twenty-six endometrial samples were evaluated. These were grouped
according to menstrual cycle phases: early proliferative [days 1–5 of
the cycle; n = 5 (2 of them menstrual)], midproliferative (days
6–10; n = 4), late proliferative (days 11–14; n = 4), early
secretory (days 15–18; n = 5), midsecretory (days 19–23; n
= 3), and late secretory (days 24–28; n = 5). The levels of IL-8
mRNA were highest in samples obtained from late secretory and early to
mid proliferative phases. The level was lowest in the late
proliferative phase and gradually increased during the secretory phase.
Overall, the mean IL-8 mRNA level (measured by laser densitometry) in
the late secretory and early to midproliferative phase samples was
significantly higher than the level observed in the middle of the cycle
(P < 0.02; Fig. 1
). In
three additional samples (two from proliferative and one from secretory
phase), we evaluated IL-8 mRNA levels in freshly separated glands and
stroma. IL-8 mRNA was detected in the glands but was undetectable in
the stroma by Northern analysis (data not shown).
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Twenty-six endometrial samples different from those used
in Northern analysis were evaluated by immunohistochemistry. The
distribution according to menstrual cycle phase was early proliferative
(n = 5), midproliferative (n = 6), late proliferative (n
= 4), early secretory (n = 5), midsecretory (n = 2), and late
secretory (n = 4). Immunohistochemistry of endometrial sections
revealed staining of the glands and surface epithelium throughout the
menstrual cycle. The staining was both membranous and cytoplasmic. The
cytoplasmic staining showed a punctate pattern. The glandular
epithelial cells of the stratum functionalis showed stronger staining
than those of the stratum basalis. We did not observe any detectable
staining in the stromal cells, although blood vessel walls were mildly
positive. There was no staining in the negative controls (Fig. 2). When staining intensities were
compared according to menstrual cycle phase, a distribution similar to
the mRNA expression was observed, although the difference was not
statistically significant (Fig. 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) may be involved
in the recruitment of the bone marrow-derived cells or their
progenitors (i.e. neutrophils, uterine large granular
lymphocytes, T cells, and monocytes) to the endometrium during
menstrual cycle. The tissue concentration of IL-8 is important in
determining whether neutrophils, lymphocytes, or both are recruited
predominantly to a specific tissue. At low concentrations of IL-8, T
lymphocytes are 2–10 times more sensitive to the chemotactic effect of
this cytokine than are neutrophils (4). IL-8 is also mitogenic and
angiogenic, two crucial events for the cyclic regenerating
endometrium. In this study, we found that IL-8 mRNA expression in the endometrium peaks during the late secretory and early to midproliferative phase. Neutrophils are known to invade the endometrium before menstruation, where these cells are probably involved in the degradation and digestion of sloughing endometrial tissue. The up-regulation of IL-8 expression in the late secretory phase may regulate this recruitment of neutrophils. We speculate that the IL-8 found in the endometrium during the early and midproliferative phase may be involved in the neovascularization of the growing endometrium, a known effect of IL-8 (5).
IL-8 protein was localized throughout the menstrual cycle to
endometrial epithelial and glandular cells, but was absent in stromal
cells. We have previously shown that endometrial glandular cells in
culture produce constitutively large amounts of IL-8 and that this
production is not regulated by IL-1 or TNF. In the present study,
immunohistochemistry results are consistent with our previous findings,
revealing the endometrial glandular expression of IL-8 protein
throughout the menstrual cycle. However, we could not detect IL-8
expression in endometrial stromal cells by immunohistochemistry,
although we had previously shown that endometrial stromal cells in
culture produce low amounts of IL-8, which is up-regulated to a
significant extent by IL-1 or TNF. As the bioavailability of most
proteins is determined by a balance between their synthesis and
degradation, we speculate that the rapid degradation of IL-8 in the
stroma may be one of the reasons for the absence of IL-8 protein in
these cells. Aminopeptidase N is a cell surface metalloprotease that
degrades and inactivates IL-8 (20). In the human endometrium, the
expression of aminopeptidase N is localized to the stroma and is not
found in the glands (21). This would also explain why despite the high
levels of IL-8 in endometrial glandular cells, the endometrium is not
continuously invaded by granulocytes. IL-8 produced by the glandular
cells may be degraded by the stroma; thus, its concentration around the
vessels may not reach the levels necessary for granulocyte
chemoattraction. Our findings are in contrast to a preliminary report
by Critchley et al. (22). In their study, IL-8
immunostaining in the endometrium was limited to smooth muscle layer of
arterioles. This finding may be due to the lack of sensitivity of the
antibody used, because even the positive controls revealed
immunostaining limited to perivascular location.
IL-8 protein expressed in endometrial epithelial cells may have many physiological roles. The immune cells chemoattracted to the surface are probably involved in the defense against pathogenic organisms. IL-8 is chemotactic for T lymphocytes at lower concentrations than required for neutrophils (4), consistent with the groups of T cells that are detected in the periglandular areas near the surface of the endometrium (23). Moreover, the secretion of IL-8 by way of the apical surface of the endometrial epithelial cells may subserve some function other than the recruitment of maternal leukocytes. Namely, an action of IL-8 on spermatozoa or on the blastocyst as well as a paracrine action on endometrial cells should be considered.
Collectively, findings from this and our previous studies suggest that 1) IL-8 is produced in the human endometrium and may modulate the recruitment of neutrophils and lymphocytes; 2) the amount of IL-8 mRNA in endometrium changes throughout the menstrual cycle, suggesting that sex steroid hormones may act directly or indirectly to regulate IL-8 expression; 3) IL-8 in human endometrium is mainly localized in glandular cells, suggesting that it may have other functions besides the recruitment of maternal leukocytes. Our findings provide a basis for future investigations on the regulation of IL-8 expression by sex steroid hormones and paracrine-acting factors (i.e. those derived from implanting trophoblasts), on potential interactions between IL-8 of the surface epithelium and blastocyst, and on the localization and regulation of enzymes that degrade IL-8.
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Footnotes |
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Received July 9, 1997.
Revised December 10, 1997.
Accepted January 15, 1998.
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, LPS, and IL-1ß. Science. 243:1467–1469.This article has been cited by other articles:
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T. Iwabe, T. Harada, T. Tsudo, Y. Nagano, S. Yoshida, M. Tanikawa, and N. Terakawa Tumor Necrosis Factor-{alpha} Promotes Proliferation of Endometriotic Stromal Cells by Inducing Interleukin-8 Gene and Protein Expression J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 824 - 829. [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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J. A. Garcia-Velasco and A. Arici Interleukin-8 expression in endometrial stromal cells is regulated by integrin-dependent cell adhesion Mol. Hum. Reprod., December 1, 1999; 5(12): 1135 - 1140. [Abstract] [Full Text] [PDF]
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S. A. Milne, H. O. D. Critchley, T. A. Drudy, R. W. Kelly, and D. T. Baird Perivascular Interleukin-8 Messenger Ribonucleic Acid Expression in Human Endometrium Varies across the Menstrual Cycle and in Early Pregnancy Decidua J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2563 - 2567. [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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