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BOR - Papers in Press, published online ahead of print November 27, 2002.
Biol Reprod 2002, 10.1095/biolreprod.102.009639
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BIOLOGY OF REPRODUCTION 68, 1491–1495 (2003)
DOI: 10.1095/biolreprod.102.009639
© 2003 by the Society for the Study of Reproduction, Inc.

Gamete Biology

Chemokine Receptor Expression in Human Endometrium1

Naciye Mulayim5, Steven F. Palter3,5, Umit A. Kayisli5,6, Levent Senturk4,5, and Aydin Arici2,5

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology,5 Yale University School of Medicine, New Haven, Connecticut 06520 Department of Histology and Embryology,6 Akdeniz University School of Medicine, 07070 Antalya, Turkey


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chemokines play a role in endometrial physiology and pathology and may affect endometrial receptivity and menstrual shedding. Chemokines exert their effect by binding to their relevant receptors, the expression levels of which may modulate their action. In the present study, we examined the expression of chemokine receptors CXCR1 and CXCR2 (receptors for interleukin-8) and CCR5 (receptor for RANTES [regulated-on-activation, normal-T-cell-expressed and -secreted], macrophage inflammatory protein [MIP]-1{alpha}, and MIP-1ß) in human endometrium. Human endometria (n = 35) were grouped according to the menstrual cycle phase and examined by immunohistochemistry for CXCR1, CXCR2, and CCR5. In both epithelial and stromal cells, CXCR1 and CXCR2 immunoreactivity was detected. Staining was most prominent at the apical and basal aspects of epithelial cells. Intense CCR5 immunostaining was observed in epithelial and stromal compartments throughout the menstrual cycle. Epithelial and stromal staining for CXCR1 reached a peak at the midsecretory phase, during which it was significantly higher than the level of staining during the proliferative phase (P < 0.05). Immunostaining for CXCR2 and CCR5 showed no significant variation across the menstrual cycle. Expression of interleukin-8 and RANTES in endometrium, together with the presence of their receptors, suggests that autocrine and paracrine interactions involving these chemokines may participate in endometrial physiology.

cytokines, female reproductive tract, menstrual cycle, uterus


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The human endometrium undergoes rapid proliferation and differentiation in response to ovarian steroid hormones. Exquisite mechanisms control these changes and direct the endometrium to a receptive state for blastocyst apposition and implantation. If implantation does not occur or fails, endometrial shedding (i.e., menstruation) ensues.

In addition to endometrial leukocytes, endometrial glands and stroma are sources as well as targets for the action of cytokines and likely are involved in menstruation and/or implantation. Interleukin (IL)-8, RANTES (regulated-on-activation, normal-T-cell-expressed and -secreted), and macrophage inflammatory protein (MIP)-1{alpha} are chemokines that are thought to be significant in endometrial physiology. The IL-8 is a cytokine with neutrophil chemotactic/activating and T-cell chemotactic activity both in vivo and in vitro [1, 2]. Its other known actions include angiogenesis [3] and mitogenesis of epidermal [4], melanoma [5], and vascular smooth muscle cells [6]. The IL-8 has been detected in the human endometrium [7, 8], choriodecidua [9], and placenta [10]. In human endometrium, IL-8 mRNA and protein expression peaks during the late secretory phase and coincides with premenstrual accumulation of leukocytes into this tissue [11, 12]. The modulation of IL-8 in human endometrium is affected by progesterone in an in vivo model [13].

The RANTES and MIP-1{alpha} are two chemokines that promote lymphocyte activation [14, 15]. The RANTES mRNA transcripts and protein are expressed in stromal cells of normal endometrium and endometriosis tissues throughout the menstrual cycle [16]. Diffuse immunoreactivity for MIP-1{alpha} expression has been shown in endometrial epithelial cells [17].

As a subclass of the cytokine family, chemokines are chemotactic proteins that are capable of inducing cell migration and activation by interacting with a superfamily of heptahelical, G-protein-coupled receptors on leukocytes. The selectivity of different chemokines is thought to depend on the ligand specificity and expression pattern of their relevant receptors, despite the fact that in vitro many chemokines bind to more than one receptor (and vice versa) [18]. Furthermore, evidence suggests that chemokine receptors play a fundamental role in the precise migration of certain types of leukocytes to the sites of inflammation. Why some subtypes of leukocytes transmigrate to inflammation areas whereas other types do not remains unclear. For instance, chemokine-receptors CXCR3 (receptor for interferon-{gamma}-inducible protein 10 and monokine induced by interferon-{gamma}) and CCR5 have been shown to be markers for T cells associated with certain inflammatory reactions, such as rheumatoid arthritis [19, 20].

To investigate possible paracrine and autocrine effects of IL-8, RANTES, and MIP-1{alpha} in different endometrial cells, including glandular, stromal, and endothelial cells, we investigated the expression of chemokine receptors CXCR1 and CXCR2 (receptors for IL-8) and CCR5 (receptor for RANTES, MIP-1{alpha}, and MIP-1ß and a coreceptor for human immunodeficiency virus) in the human endometrium by immunohistochemistry. In the present study, we have described the localization and variability of these receptors throughout the menstrual cycle.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Collection of Tissue

Endometrial tissue was obtained from 35 normally cycling, fertile women (age: mean ± SD, 42.5 ± 4.6 yr; range, 34–49 yr) undergoing laparoscopy or hysterectomy for benign gynecological conditions other than endometrial disease at Yale New Haven Hospital. 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 women's menstrual history and was confirmed by endometrial histology using published criteria [21].

During laparoscopy, endometrial tissues were collected either by sharp curettage or Pipelle biopsy. After hysterectomy, the uterus was opened, and multiple sections, including the myometrium, were obtained. Indications for the surgery were as follows: tubal ligation (15 patients), leiomyomata (13 patients), benign adnexal mass (5 patients), pelvic pain (3 patients), and cervical intraepithelial neoplasia (2 patients). These women had no visible pelvic inflammation or endometriosis at laparoscopy or laparotomy. Samples were grouped according to menstrual cycle phases: proliferative (Days 1–14 of the cycle, n = 12), early secretory (Days 15–18, n = 8), midsecretory (Days 19–23; n = 8), and late secretory (Days 24–28; n = 7).

Immunohistochemistry

Endometrial tissue samples (n = 24) were snap-frozen in OCT (Tissue Tek; Sakura, Torrance, CA). Serial cryosections (thickness, 6–8 µm) were placed on poly-L-lysine-coated glass microscope slides and fixed at 4°C in acetone for 5 min. Sections were rinsed twice in phosphate-buffered saline (PBS; pH 7.4) for 5 min each and in PBS with bovine serum albumin (PBS-BSA; 0.1% [wt/vol]) for 10 min. Endogenous peroxidase activity was quenched with 0.6% H2O2 in PBS (vol/vol) for 15 min. Slides were then incubated with 4% blocking horse serum (Vector Laboratories, Burlingame, CA) for 1 h at room temperature in a humidified chamber. Excess serum was drained, and primary antibodies (murine monoclonal anti-human CXCR1 antibody immunoglobulin [Ig] G2B, clone 5A12 [Pharmingen, San Diego, CA], 500 µg/ml, 1:300 dilution in PBS-BSA; murine monoclonal anti-human CXCR2 antibody IgG2A clone 8311.211 [R&D Systems, Minneapolis, MN], 500 µg/ml, 1:300 dilution in PBS-BSA; and murine monoclonal anti-human CCR5 antibody IgG2B clone 45523.111 [R&D Systems], 500 µg/ml, 1:50 dilution in PBS-BSA) were added to the sections. For the negative control, normal mouse IgG isotypes were used at the same concentrations. Neutrophils were used for positive control for CXCR1 and CXCR2, and peripheral blood lymphocytes were used for positive control for CCR5. Sections were incubated overnight at 4°C in a humidified chamber. The sections were rinsed, then biotinylated horse anti-mouse antibody (1.5 mg/ml; Vector Laboratories) was added at a 1:250 dilution for 45 min at room temperature. The antigen-antibody complex was detected by 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 and mounted with Permount (Fisher Chemicals, Springfield, NJ) on glass slides.

Immunohistochemical staining for CXCR1, CXCR2, and CCR5 was evaluated in a semiquantitative fashion (i.e., 0 [absent] to 3 [most intense]). Epithelial and stromal cells were separately scored. Vascular and myometrial cells were individually evaluated. For each slide, an HSCORE value was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of the staining—that is, HSCORE = {Sigma}Pi(i + 1), where i is the intensity score and Pi is the corresponding percentage of the cells. In each slide, five different areas were evaluated under a microscope (50x magnification), and the percentage of the cells for each intensity within these areas was determined by two investigators at different times. The average score of the two was used.

Statistical Analysis

Epithelial and stromal HSCORE values were normally distributed (Kolmogorov-Smirnov test). The statistical differences in HSCORE values among various phases of the menstrual cycle were analyzed using one-way ANOVA and the post-hoc Bonferroni test for pairwise multiple comparisons. All statistical analyses were performed using Sigmastat for Windows, version 2.0 (Jandel Scientific Corporation, San Rafael, CA). Data are presented as the mean ± SEM. Differences were considered to be significant at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
CXCR1 and CXCR2 Expression in the Endometrium

Thirty-four endometrial samples were evaluated by immunohistochemistry for CXCR1 and CXCR2. Samples were obtained from women in the proliferative (n = 11), early secretory (n = 8), midsecretory (n = 8), and late secretory (n = 7) phases of the menstrual cycle. Diffuse and intense CXCR1 immunoreactivity was localized in the surface epithelium and glands throughout the menstrual cycle in all samples. The staining was membranous and was most intense at the apical and basal surfaces of the glands (Fig. 1a). Glandular cells of the basal layer of the endometrium showed weaker staining than those of the functional layer during all phases of the menstrual cycle (Fig. 1b). Stroma stained with a relatively lesser intensity compared to the epithelial cells. In the functional layer, the staining of the stroma was diffuse and membranous. In the basal layer, the staining pattern of the stroma changed into focal membranous and cytoplasmic staining. Distinct staining in the myometrium and moderate staining in the vascular wall were noted in all samples (Fig. 1, b and b insert).



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  		FIG. 1. Representative micrographs of immunohistochemistry staining for CXCR1 in the human endometrium during menstrual cycle phases. During the proliferative phase (a), endometrium shows predominantly weak epithelial immunoreactivity for CXCR1 (functional layer). Glandular staining in the basal layer of the endometrium is weaker than that of the functional layer (b). Myometrium and vascular cells are distinctly stained (b insert). A higher staining intensity in both epithelium and stroma is noted in secretory endometrium (c and c insert). Bars = 50 µm

We observed significant variation in CXCR1 immunoreactivity in the epithelial and stromal cells related to the menstrual cycle phase. The epithelial immunostaining HSCORE value was higher during the secretory phase compared to the proliferative phase (Fig. 1, a, c, and c insert). The level of staining reached a peak during the midsecretory phase, when it was significantly higher than the level of staining during the proliferative phase (P < 0.05) (Fig. 2a). Stromal staining for CXCR1 showed a similar pattern of variation throughout the cycle, with higher HSCORE values during the midsecretory phase compared to the proliferative phase (P < 0.05) (Fig. 2b). No significant cycle phase variation was observed in the staining intensity of vascular structures or the myometrium across the menstrual cycle in 23 samples.



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  		FIG. 2. The distribution of immunostaining intensity (HSCORE) in endometrial glands (a) and stromal cells (b) with murine monoclonal anti-human CXCR1 antibody according to the menstrual cycle phase. Data represent the means of HSCORE given to each sample in the respective menstrual cycle phase, and error bars represent the SEM. P, Proliferative; S1, early secretory; S2, midsecretory; S3, late secretory. *P < 0.05 between proliferative and midsecretory phase in pairwise comparison

Localization of immunostaining for CXCR2 in the epithelium and stroma was similar to the localization observed for CXCR1 (Fig. 3a). No stromal CXCR2 immunoreactivity was visualized in some samples. Myometrium stained strongly, whereas vascular cells of arterioles, venules, and capillaries showed no staining in most samples. No significant variation in epithelial or stromal HSCORE values was noted across the menstrual cycle (data not shown). Myometrial staining HSCORE values in 23 tissue samples demonstrated no variation among various phases of the cycle.



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  		FIG. 3. a) Representative micrograph of immunohistochemistry staining for CXCR2 in proliferative endometrium. Membranous staining is observed in apical and basal aspects of epithelial cells, whereas stroma is only weakly stained. Vascular cells reveal no immunoreactivity. b) Representative immunoreactivity of proliferative endometrium for CCR5. Diffuse epithelial and stromal immunoreactivity is noted. Bars = 50 µm

CCR5 Expression in the Endometrium

Immunostaining for CCR5 was performed on 33 endometrial samples. Distribution of samples across the cycle were as follows: proliferative, n = 11; early secretory, n = 7; midsecretory, n = 8; and late secretory, n = 7. Diffuse and intense CCR5 immunostaining of the surface epithelium and glands was observed throughout the menstrual cycle (Fig. 3b). The staining was primarily membranous, with lesser cytoplasmic staining being visible. The staining was most prominent at the apical and basal membranes of epithelial cells. The glandular cells of the functional layer showed more intense staining than those of the basal layer (data not shown). Stromal cells revealed membranous and cytoplasmic staining (Fig. 3b). In the functional layer, the staining of the stroma was homogenous, whereas in the basal layer, it was confined to focal areas. The cells of arterioles, venules, and capillaries as well as the myometrium exhibited distinct staining. Analysis of HSCORE values for epithelial, stromal, vascular, or myometrial cell staining in 21 tissue samples revealed no significant variation across the menstrual cycle (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In recent years, studies have shown that regulated action of cytokines is crucial in preparing the endometrium for implantation or menstruation. Besides affecting the migration and activation status of leukocytes, cytokines may be involved in a variety of other actions, including cell proliferation, angiogenesis, and regulation of metalloproteinase and integrin expression.

Chemokines exert their effect by binding to their appropriate receptors. Understanding the role of each chemokine in physiology or disease is rendered difficult because chemokines show overlapping specificities. The selectivity of different chemokines largely depends on the ligand specificity and expression pattern of their relevant receptor [18]. A recent report described the expression of the chemokine eotaxin and its receptor, CCR3, in human endometrium [22]. In the present study, we have shown, to our knowledge for the first time, the protein expression of chemokine-receptors CXCR1, CXCR2, and CCR5 in human endometrium. Iwabe et al [23] have previously demonstrated the expression of CXCR1 mRNA in endometrial and endometriotic stromal cells, but we believe the present study to be the first report of CXCR1 protein expression.

Receptors for IL-8 differ in their ligand specificity: CXCR1 binds selectively to IL-8 and granulocyte chemotactic protein-2 with high affinity [24, 25], whereas CXCR2 binds with high affinity to IL-8 and other chemokines, such as neutrophil-activating peptide-2 and melanoma growth stimulatory activity [26, 27]. The IL-8-receptor system is a good example with which to show that chemokine receptors may regulate chemokine-mediated activities of the cell. In polymorphonuclear leukocytes, CXCR1 and CXCR2 mediate different functional responses to IL-8. Changes in intracellular calcium concentration ([Ca2+]i), the release of granule enzymes, and chemotaxis in response to IL-8 are mediated through both receptors. In contrast, O2- release and the activation of phospholipase D in response to IL-8 depend exclusively on CXCR1 [28–31].

The CXCR1 and CXCR2 show different characteristics of desensitization by their ligand IL-8. The affinity of CXCR1 for IL-8 is lower than that of CXCR2, and it requires 7- to 13-fold more IL-8 to down-regulate CXCR1 than CXCR2. The recovery rate of CXCR1 expression is rapid after desensitization by IL-8, whereas that of CXCR2 is slow. The rapid re-expression of CXCR1 suggests that this receptor may play a more active role in mediating IL-8 signal at the site of inflammation, where the concentration of IL-8 is high. On the other hand, the high-affinity CXCR2 may initiate the neutrophil migration in a distant area of inflammation, where the concentration of IL-8 is low [32]. This information may potentially explain why we found a much greater expression of CXCR1 in comparison to CXCR2: A high level of IL-8 production occurs in the human endometrium; therefore, CXCR1, by being relatively difficult to down-regulate and easy to re-express, becomes the predominant IL-8 receptor at this site.

The IL-8 is predominantly expressed in the apical aspects of endometrial epithelial cells, the site where initial embryo attachment takes place [11]. Its expression in human endometrium peaks during the late secretory phase and coincides with premenstrual migration of leukocytes into this tissue [11, 12]. The bioavailability of IL-8 in human endometrium is suggested to be regulated by aminopeptidase N, an IL-8-inactivating enzyme produced by endometrial stromal cells as well as a variety of immune cells [33]. In the present study, we observed that the immunolocalization of CXCR1 and CXCR2 in human endometrium is similar to that of their ligand IL-8. The expression of CXCR1 in endometrial epithelium and stroma shows variation throughout the menstrual cycle, reaching a peak during the midsecretory phase. All these findings suggest that the IL-8 ligand-receptor system is under the direct or indirect control of sex steroids and that it may be effective in directing the endometrium to a receptive state for embryo implantation or in leading it to menstruation. The precise mechanism by which the IL-8 ligand-receptor system affects these physiological events is unclear.

Cross-talk between chemokine receptors and integrins is known to occur and may have important implications during the transmigration of neutrophils into the extracellular matrix. Recently, it has been shown that IL-8 triggers firm adhesion of monocytes to vascular endothelium through activation of specific leukocyte integrins, and this effect is mediated by CXCR1 and CXCR2 present on monocytes [34]. Thus, cross-talk between IL-8 receptors and integrins may be operative in the attachment/invasion of the blastocyst to the endometrium or in the trafficking of immune cells in this tissue.

In the present study, we have localized CCR5 to both endometrial epithelium and stroma. The CCR5 ligands RANTES and MIP-1{alpha} have previously been detected in human endometrium [16, 17]. The production of RANTES by cultured human endometrial cells is stimulated by lipopolysaccharides, tumor necrosis factor {alpha} (TNF{alpha}) and IL-1ß and is inhibited by IL-4 [35]. Besides agonist-induced desensitization, modifiers of CCR5 expression are IL-2 and TNF{alpha} [36, 37]. Hornung et al. [16] reported expression of RANTES in endometrial epithelial cells in the luteal phase and endometrial stromal cells throughout the menstrual cycle. To our knowledge, no data are available regarding steroid regulation of MIP-1{alpha} in human endometrium, and we have not been able to show any variation in CCR5 expression throughout the menstrual cycle in the present study.

In conclusion, we identified, to our knowledge for the first time, the expression of CXCR1, CXCR2, and CCR5 proteins in human endometrium. Expression of IL-8 and RANTES, together with the presence of their receptors, raises the possibility that autocrine and paracrine interactions involving these chemokines may participate in endometrial modeling during the menstrual cycle and implantation.


   FOOTNOTES
 
1 Part of this work is from the Ph.D. thesis of U.A.K Back

2 Correspondence: Aydin Arici, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Yale University School of Medicine, New Haven, CT 06520. FAX: 203 785 7134; aydin.arici{at}yale.edu Back

3 Current address: Reproductive Medicine and Surgery Center, Plainview, NY 11803 Back

4 Current address: Istanbul University Cerrahpasa School of Medicine Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology Cerrahpasa, Istanbul, Turkey Back

Received: 22 July 2002.

First decision: 15 August 2002.

Accepted: 3 November 2002.


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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Y.-L. Shi, X.-Z. Luo, X.-Y. Zhu, K.-Q. Hua, Y. Zhu, and D.-J. Li
Effects of combined 17beta-estradiol with TCDD on secretion of chemokine IL-8 and expression of its receptor CXCR1 in endometriotic focus-associated cells in co-culture
Hum. Reprod., April 1, 2006; 21(4): 870 - 879.
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 Hum Reprod UpdateHome page
E. Dimitriadis, C.A. White, R.L. Jones, and L.A. Salamonsen
Cytokines, chemokines and growth factors in endometrium related to implantation
Hum. Reprod. Update, November 1, 2005; 11(6): 613 - 630.
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R. L. Jones, N. J. Hannan, T. J. Kaitu'u, J. Zhang, and L. A. Salamonsen
Identification of Chemokines Important for Leukocyte Recruitment to the Human Endometrium at the Times of Embryo Implantation and Menstruation
J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6155 - 6167.
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