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Original Articles: Hormones and Reproductive Health |
Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, and Division of Reproductive Endocrinology, Yale University School of Medicine, New Haven, Connecticut 06520
Address all correspondence and requests for reprints to: Steven F. Palter, M.D., Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208063, New Haven, Connecticut 06520. E-mail: steven.palter{at}yale.edu
Abstract
The human fallopian tube is a dynamic structure that undergoes cyclic variation in its functional epithelium. This epithelium contains both secretory and ciliated cells. The mechanisms regulating the growth and function of the tubal epithelium are not fully understood. Interleukin-8 (IL-8) is one potential local regulatory factor. We therefore characterized the IL-8 system, which includes IL-8, its receptors A and B, and its degradative enzyme aminopeptidase N, in the human fallopian tube by immunohistochemistry. Immunohistochemistry was performed on isthmic, ampullary, and fimbrial fallopian tubal segments obtained from women undergoing gynecological surgical procedures for benign conditions (n = 52). IL-8 was found in the human fallopian tube predominantly in the epithelial cells. It was present in greater amounts in the distal compared with the proximal tube. IL-8 receptors A and B localized in the tube in similar patterns. The degradative enzyme aminopeptidase N is found in tubal stromal tissue at the epithelial stromal border and perivascularly and may limit the systemic effects of epithelial IL-8. The IL-8 system seems to be an active component of tubal physiology.
THE FALLOPIAN TUBE, a dynamic muscular tube with an epithelial lining, is the site of gamete transport, maturation, and fertilization as well as early embryo development and transport. Far from functioning as a passive conduit to gametes and embryos, the fallopian tube actively secretes multiple substances, has an active ciliated epithelium, and undergoes muscular contractions (1).
Diseased tubes are associated with decreased fecundity and may be the site of ectopic gestations. The tubal epithelial lining is composed of two populations of differentiated cells: one nonciliated and secretory, and one ciliated. Distinction between the cell types is not absolute, with occasional cells demonstrating both cilia and secretory capacities in nonhuman studies (2). The secretory function of the tube remains incompletely characterized. The tube is commonly divided into four anatomical segments (3). The most proximal intramural segment courses through the wall of the uterus. The isthmic segment lies immediately outside of the uterus and extends to the point where the tube is seen to widen externally, with thick muscular layers and a relatively narrow lumen. The distal two thirds of the fallopian tube is visibly wider than the isthmus and comprises the ampulla, which has a wider lumen and thinner muscular layers than the isthmus. The most distal portion of the tube is the fimbrae, which are the folds that contact the ovary.
The entire length of tubal epithelium undergoes cyclic variation across the menstrual cycle (1, 4, 5, 6). Cell height and cellular population percentages as well as mitotic activity vary significantly across the cycle. Circulating ovarian sex steroids may regulate these cyclic changes; however, the mechanism of action of these steroids (direct or indirect via growth factors and cytokines) remains largely unknown. Studies of other active epithelia (such as in the gastrointestinal tract and endometrium) have demonstrated central roles for local regulatory substances governing similar functions (7, 8).
Chemokines are a large family of chemotactic cytokines with molecular
masses between 8–10 kDa. As soluble chemoattractant molecules, they
attract leukocytes (8, 9). Interleukin-8 (IL-8) is a
member of the 
, or CXC, subfamily, so classified based on the
spacing of the second and fourth cysteine residues (C-C) with an
intervening amino acid (X) in the amino-terminus region
(9). The CXC chemokines particularly attract and activate
neutrophils and include IL-8, melanoma growth-stimulating activity
(MGSA), GRO-, and platelet factor-4 (10). In addition
to its proinflammatory effects, IL-8 is mitogenic for endometrial cells
as well as for epidermal, melanoma, and vascular smooth muscle cells
(11, 12, 13, 14). IL-8 also causes angiogenesis via chemotaxis of
endothelial cells (11).
Peripheral blood monocytes, endothelial cells, fibroblasts,
neutrophils, keratinocytes, synovial cells, mesothelial cells, and
endometrial glandular cells all produce IL-8 (15, 16, 17, 18, 19). In
the human endometrium IL-8 is present by immunohistochemistry (IHC)
staining in the glandular and surface epithelium and is secreted by
endometrial stromal and epithelial cells in culture (15).
IL-1 and tumor necrosis factor- regulate the production of IL-8 from
these cells in vitro, and secretion in vivo
varies across the menstrual cycle (20). The presence of
IL-8 in human fallopian tube tissue has not previously been
described.
Two specific membranous receptors mediate the effects of IL-8 (10, 21, 22, 23, 24). These G protein-coupled receptors are classified as IL-8 receptor A (IL-8RA) and IL-8 receptor B (IL-8RB). These receptors share 77% amino acid sequence identity, but differ in their ligand specificities (10, 22). IL-8RA preferentially binds IL-8, whereas IL-8RB also binds other chemokines, such as MGSA and neutrophil-activating protein-2, with equal affinity (10, 23).
Aminopeptidase N (APN; arylaminidase), also known as CD13, is a single chain 150-kDa membrane glycoprotein with metalloproteinase activity that functions as the primary degradative enzyme for IL-8 (25, 26, 27). APN is expressed on the cell surface of many cell types and cleaves IL-8, thereby inactivating its chemotactic activity in vitro. Inactivation of IL-8 is one mechanism controlling the chemotactic activity of IL-8. To date, the presence of the IL-8 receptors and APN has not been reported in the fallopian tube.
We hypothesized that the human fallopian tube produces and secretes IL-8, which may have autocrine growth-regulating and/or chemokine activity. We first conducted IHC of human fallopian tube segments throughout the menstrual cycle and identified IL-8 and its receptors, IL-8RA and IL-8RB. Next, we assessed the presence of APN by IHC. We finally identified macrophages in the tube via IHC staining with CD68, because they also produce IL-8 and may participate in this system.
Materials and Methods
Tissue collections and experimental subjects
Fallopian tubes were obtained from cycling women undergoing tubal ligations or hysterectomy conducted for benign gynecological conditions (excluding tubal pathology) at Yale-New Haven Hospital. Isthmic tubal segments were obtained 2 cm from the cornua, ampullary segments were obtained 2 cm from the fimbrial segment, and frimbrial segments were obtained from the distal 1 cm of the tube. Tubes with gross pathology were not collected for this study. Tissue was immediately collected into Hanks’ Balanced Salt Solution on ice in the operating room and then frozen in OCT (Tissue-Tek, Sakura, Torrance, CA) in isopentane and liquid nitrogen within 1 h of collection. Informed consent was obtained, and the human investigation committee of Yale University School of Medicine approved the protocol. Endometrial tissue from the subjects was submitted for histological examination, and menstrual cycle day was established using the criteria reported by Noyes et al. (28). Dating characterized the samples as early proliferative (days 1–5 of the cycle), midproliferative (days 6–10 of the cycle), late proliferative (days 11–14 of the cycle), early secretory (days 15–18), midsecretory (days 19–23), and late secretory (days 24–28) phases of the menstrual cycle. In many cases all three tubal segments were not available from a given subject.
IHC staining
Tissues were sectioned in 6-µm sections on a cryostat and placed on poly-L-lysine-coated glass microscope slides for IHC. Tissue sections were fixed in acetone at 4 C for 5 min and rinsed twice in PBS (pH 7.4) for 5 min each time and then in PBS-BSA (0.1%, wt/vol) for 5 min. Nonspecific staining was reduced via incubation with 4% blocking normal horse serum (Vector Laboratories, Inc., Burlingame, CA) for 1 h at room temperature in a humidified chamber. Excess serum was drained, and the primary antibodies were applied. The tissue was incubated overnight at 4 C in a humidified chamber with specific monoclonal murine IgG1 antibodies.
For IL-8 IHC, a specific monoclonal antibody directed against human IL-8 was used (murine monoclonal antihuman IL-8, clone Nap II, IgG1; 10 µg/mL; Bender Med Systems, Vienna, Austria). For chemokine receptor IHC, specific monoclonal murine IgG1 antibodies directed against human IL-8-RA and IL-8-RB were used as follows: 1) murine monoclonal antihuman CXCR-1 (IL-8 RA) antibody IgG2B, clone 5A12 (PharMingen, San Diego, CA), 50 µg/mL, 1:300 dilution in PBS-BSA; and 2) murine monoclonal antihuman CXCR-2 (IL-8 RB) antibody IgG2A clone 8311.211, 500 µg/mL, 1:300 dilution in PBS-BSA (R\|[amp ]\|D Systems, Inc., Minneapolis, MN). For APN, a specific monoclonal murine IgG1 antibody directed against human APN/CD13 [murine monoclonal antihuman myeloid cell antibody, clone VS5E, 1:50 dilution (Novocastra Laboratories, Newcastle Upon Tyne, UK)] was used. To identify macrophages within the fallopian tube, IHC staining was performed with CD68 (murine monoclonal antihuman macrophage antibody, IgG1, clone EBM11; DAKO Corp., Carpinteria, CA; 395 µg/mL; 1:100 dilution in PBS-0.1% BSA).
Initial experiments were performed to determine the optimal primary antibody concentrations for each antibody in human fallopian tube sections. For the negative control, nonspecific mouse IgG was used at the same concentrations. Endogenous peroxidase activity was quenched with 0.6% H2O2 in PBS (vol/vol) for 15 min. Sections were rinsed and then incubated with biotinylated horse antimouse IgG (1.5 mg/mL; Vector Laboratories, Inc.) for 45 min in humidified chambers at room temperature. The antigen-antibody complex was detected using an avidin-biotin peroxidase kit (Vector Laboratories, Inc.). Freshly diluted filtered diaminobenzidine (3,3-diaminobenzidine tetrahydrochloride dihydrate, Aldrich Chemical Co., Inc., Milwaukee, WI)/hydrogen peroxide (0.5 mg diaminobenzidine in 0.03% H2O2 in PBS) was used as the chromogen, and sections were counterstained with hematoxylin and mounted with Permount (Fisher Scientific, Springfield, NJ) on glass slides.
IHC staining was scored by two evaluators blinded to the sample’s menstrual phase and the subject’s clinical history in a semiquantitative fashion incorporating both intensity and the distribution of staining (29). 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 negative control), 2+ (distinct), and 3+ (intense). Epithelial and stromal cells were separately scored. Where applicable, staining intensity was evaluated for the overall epithelium, apical surface of the epithelium, basal surface of the epithelium, stroma, perivascular area, and tubal muscular layer. For each tissue, an HSCORE value was derived by summing the percentages of cells that stained at each intensity multiplied by the weighted intensity of the staining [HSCORE = Pi(I + 1), where i is the intensity score, and Pi is the corresponding percentage of the cells]. Macrophages stained with CD68 antibody were counted using an Olympus Corp. microscope (New Hyde Park, NY) with a special ocular grid.
Statistical analyses
Epithelial and stromal HSCOREs were compared using Kruskal-Wallis one-way ANOVA on ranks or one-way ANOVA for staining scores as applicable. One-way ANOVA was used when scores were normally distributed and with equal variance, as tested by the Kolmogorov-Smirnov test. When significant differences between groups were found, post-hoc multiple comparison tests were used to isolate these differences. Multiple comparisons were performed with Tukey’s test or Dunn’s (when group sizes were unequal). All statistical analyses were performed using SigmaStat version 3.02 (SPSS, Inc., Chicago, IL), with significance at the P < 0.05 level.
Results
IL-8 immunohistochemistry in the fallopian tube
We evaluated 37 fallopian tube samples by IHC for IL-8. Samples
were from the isthmic (n = 10), ampullary (n = 16), and
fimbrial (n = 11) portions of the tube. Samples were taken from
women in various phases of the menstrual phase as judged by endometrial
histological dating. We obtained samples from women in the early
proliferative (n = 10), midproliferative (n = 9), late
proliferative (n = 4), early secretory (n = 5), midsecretory
(n = 6), and late secretory (n = 3) phases of the menstrual
cycle. There was diffuse IHC staining for IL-8 of the surface
epithelium throughout the fallopian tube (Fig. 1
, A–D). This staining was primarily
membranous, with lesser cytoplasmic staining visible. The membranous
staining was most intense at the apical membranes. In contrast, the
stroma was predominantly negative for staining. Isolated cells with the
morphological characteristics of macrophages stained positively in the
stroma of selected sections. Distinct staining was also visible in the
tubular muscular wall as well as, to a lesser extent, in the endothelia
of blood vessels. There was no significant variation in the staining
intensity in the vascular structures or the muscle across the menstrual
cycle. The negative controls had no distinct staining.
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). Apical membrane staining was
significantly greater in the distal than in the proximal segments, but
the difference was not significant for basal membrane staining along
the different tubal segments. There was no significant variation in
total HSCOREs or apical HSCOREs among different phases of the menstrual
cycle. In contrast, there was significantly higher basal membrane
staining in the late proliferative vs. late secretory phase
samples (P = 0.007; Fig. 3).
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We evaluated 33 fallopian tube samples by IHC for IL-8RA. The
samples were from the isthmic (n = 11), ampullary (n = 11),
and fimbrial (n = 11) portions of the tube. Endometrial
histological dating of the samples was early proliferative (n =
15), midproliferative (n = 4), late proliferative (n = 3),
early secretory (n = 4), midsecretory (n = 3), and late
secretory (n = 4) phases of the menstrual cycle. There was diffuse
IL-8RA IHC staining of the surface epithelium throughout the tube (Fig. 1
, E–H). This staining was membranous and was most intense at the
apical membranes. Epithelial staining was observed in all three tubal
segments. Membranous stromal staining was also observed, but at a
greatly reduced intensity than that of epithelial staining. Distinct
staining was also visible in the muscular cells of the tubal wall and
vascular structures. The vessel endothelium did not exhibit IHC
staining. No distinct staining was observed in the negative
controls.
Similar to IL-8, when HSCOREs were compared among the different tubal
segments there was significantly greater staining in the distal
(fimbria) vs. proximal (isthmic) tube (P =
0.029; Fig. 4). We observed no
significant variation in epithelial staining HSCOREs in tubal samples
obtained from different phases of the menstrual phase. There was no
significant variation in stromal staining HSCOREs across either tubal
segments or phases of the menstrual cycle. There was no staining
observed in the negative controls.
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, A and B). In contrast to IL-8 and IL-8
RA, epithelial staining for IL-8RB was in a patchy, rather than a
continuous, pattern. The distribution of staining along the length of
the fallopian tube for IL-8RB was similar to that of IL-8 and IL-8RA,
with significantly greater staining in the distal than in the proximal
tube (P = 0.045; Fig. 6).
We observed a trend toward a variation in the staining intensity among
the phases of the menstrual cycle with a midcycle nadir; however, this
did not reach statistical significance (Fig. 7). There was only minimal stromal
staining observed without cycle or segment variation. There was no IHC
staining observed in the blood vessels or muscular wall of the tube or
in the negative controls.
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Thirty fallopian tube samples were evaluated by IHC for APN. The
samples included the isthmic (n = 10), ampullary (n = 9), and
fimbrial (n = 11) portions of the fallopian tube. Samples were
from subjects in the early proliferative (n = 10),
midproliferative (n = 5), late proliferative (n = 3), early
secretory (n = 3), midsecretory (n = 5), and late secretory
(n = 4) phases of the menstrual cycle. We observed APN IHC
staining in all segments of the fallopian tube. The staining was
present in both epithelium and stroma of the tube, but was
preferentially located in a distinct linear stromal band at the
epithelial-stromal junction (Fig. 5C). Stromal staining was also
observed to a lesser extent in the perivascular stromal tissue (Fig. 5D). Stromal staining was uniformly present in tubal segments, whereas
the vast majority of tubal segments did not demonstrate epithelial
staining. In cases where epithelial staining was present, it was seen
in a small focal patchy distribution. No variation in epithelial or
stromal HSCOREs was observed between tubal segments or menstrual cycle
phases, and there was no staining of the negative controls.
IHC localization of macrophages in the fallopian tube
We evaluated 52 fallopian tube samples by IHC for the presence of
macrophages via staining with CD68. The tubal samples were taken from
the isthmic (n = 16), ampullary (n = 18), and fimbrial
(n = 18) portions of the fallopian tube. Samples were from women
in the early proliferative (n = 16), midproliferative (n =
6), late proliferative (n = 4), early secretory (n = 6),
midsecretory (n = 2), and late secretory (n = 5) phases of
the menstrual cycle. We obtained an additional 13 samples from subjects
for whom endometrial dating was not available. We identified
macrophages in most tubal segments by CD68 staining, and they localized
to the stromal tissue of the different tubal segments (Fig. 5, E and
F). The majority of the samples examined contained relatively few
macrophages, whereas selected samples had a higher concentration. We
did not observe significant differences in the number of macrophages
present in the different tubal segments or in tubal segments from
different phases of the menstrual cycle. The distribution of
macrophages observed did not correspond to the majority of the IL-8 or
IL-8R staining.
Discussion
The fallopian tube is far from a hollow passive conduit for gametes. Rather, the tube plays an active role in the reproductive system and undergoes continual cyclic epithelial changes. Despite a central role in natural fertilization, relatively little is known about regulation of the changes observed in the tubal epithelium. To date, the changes described include cell populations, ciliation, cell height, secretion, and muscular contractions (1). Although it has been postulated that circulating ovarian sex steroids regulate these cyclic changes, direct effects have yet to be demonstrated. In addition, ciliated tubal epithelial cells do not express classical estrogen receptors (1). For these reasons, a putative role of local regulatory factors has been postulated.
IL-8 displays potent chemoattractant and cellular activating properties and is therefore classified as a chemokine. It is produced locally in the human female reproductive tract and has been localized to endometrial epithelial and stromal cells (8, 14, 15). In the human endometrium, IL-8 has been localized by IHC to the glandular and surface epithelium and is produced by endometrial stromal and epithelial cells in culture (20). A menstrual cycle-related variation in IL-8 messenger ribonucleic acid expression peaks in the late secretory and early to midproliferative phases (15). IL-8 potentially regulates leukocyte recruitment into the endometrium, and its up-regulation at the end of the menstrual cycle may regulate the influx of neutrophils before menstruation. The rise in IL-8 in the early proliferative phase may contribute to neovascularization of the endometrium (11, 15).
We observed IL-8 in the human fallopian tube via IHC staining, and it was predominantly localized to tubal epithelial cells. In addition, there was a significant increase in staining in the distal compared with the proximal tube. Previously, IL-8 was demonstrated via enzyme-linked immunosorbent assay in human tubal fluid, probably secreted by tubal epithelial cells (30).
The segmental variation observed may represent differences in the populations of epithelial cells present in each location. Some reports have suggested that secretory activity is maximal in the isthmus, where a higher proportion of epithelial cells may be secretory, whereas ciliation is probably maximal in the distal tube (4, 6). Exact identification of ciliated vs. secretory cells was not possible in our study via light microscopy and would require either immunoelectron microscopy or IHC staining with additional specific cellular subtype markers.
We also observed a variation in IL-8 IHC staining across the phases of the menstrual cycle. The preovulatory peak coincides with the peaks in cell height, secretion, and ciliation observed at this time. Notably, the epithelium reaches maximal height and secretory activity in the late preovulatory proliferative phase, whereas secretion decreases after ovulation in the luteal phase (4, 31). Donnez et al. demonstrated that ciliation is maximal in the late follicular period, followed by low levels of ciliation in the luteal phase of the cycle (6). At the end of the luteal phase epithelial cell height diminishes to its lowest, and ciliation and secretion are both maximally suppressed (4, 5, 32, 33).
Although the epithelial changes occur across the menstrual cycle
coincident with variations in estrogen and progesterone, several
investigators suggested that growth factors might mediate the observed
changes, especially as estrogen receptors have not been identified in
ciliary cells (1, 5, 6, 34, 35). Smotrich et
al. localized transforming growth factor- to tubal epithelial
cells via IHC, with weak staining observed in stromal tissues
(35). In contrast, epidermal growth factor receptors did
not localize to the tubal cells. Others have identified insulin-like
growth factor I, its binding proteins, and its receptor in the
fallopian tube (34, 36, 37). IL-8’s distribution, namely
predominantly epithelial apical membranous IHC positivity, resembles
the distribution of epidermal growth factor previously described
(38). This study suggests that IL-8 may serve as one such
local regulatory cytokine.
Several fundamental physiological differences exist between the endometrium and the fallopian tube. Specifically, the endometrium contains a population of resident and migratory lymphocytes. After ovulation, an influx of large granular lymphocytes occurs that may participate in the IL-8 system (8). We performed IHC staining for macrophages using CD68 as a marker to determine whether macrophages were involved in the expression of IL-8 in the tube. Our observations did not reveal such an influx in the tube. Although macrophages were on occasion observed in the tubal segments, their distribution was different than that of IL-8 and its receptors.
Several groups described increased cleavage rates and improved outcomes when they cocultured human in vitro fertilized embryos on cellular monolayers, including tubal epithelial cells (39). IL-8 may play an interactive role with gametes or embryos in addition to a local regulatory role in the tubal epithelium. In contrast, clinical in vitro fertilization outcomes may be reduced in cases where hydrosalpinges are present (40). As IL-8 may play a role in inflammatory conditions, tubal infections and subsequent hydrosalpinx formation may lead to altered local or secreted levels of IL-8, which may be embryotoxic.
Tubal scarring and adhesions are other sequellae of pelvic inflammatory disease. These are most commonly associated with infections by Neisseria gonorrhea or Chlamydia trachomatis in women. Tubal epithelial IL-8 may play an additional role in this setting as a barrier to ip infection from ascending cervical pathogens. The host response to a primary chlamydial infection of a mucosal surface is acute inflammation and is characterized by infiltration of neutrophils and monocytes (41). In animal models of ophthalmological chlamydial infection, the host’s inflammatory reaction can eliminate the infectious organism, whereas in reinfection the host’s inflammatory response occurs more rapidly and with greater T cell infiltration (41). In the gastrointestinal tract it has been postulated that the epithelial cells, which secrete proinflammatory cytokines, play a defensive role against infection (42). Rasmussen et al. demonstrated in vitro that infection and intracellular growth of Chlamydia trachomatis in cervical epithelial cells triggered a sustained production and secretion of cytokines, including IL-8 from the epithelial cells (41). In this regard, IL-8 in the tube may play a similar defensive role.
CXCR-1 and CXCR-2 were the first two chemokine receptors cloned in 1991
and were first identified on neutrophils (10). CXCR-1
(IL-8R-A) is more specific for IL-8 and will bind other cytokines with
much lesser affinity. CXCR-2 (IL-8RB) is less specific for IL-8 and, in
addition, binds neutrophil-activating polypeptide-2, 78-amino acid
epithelial neutrophil activating factor, and MGSA/GRO- as well as
GRO-ß and -
(8, 23, 24). The presence of IL-8RA and
IL-8RB in the epithelial layer of the fallopian tube suggests that IL-8
may have an autocrine effect on these cells. A similar growth-promoting
effect of IL-8 was described in other cells types, such as endometrium
(14).
APN (CD13) is the primary degradative enzyme for IL-8 (27). It is a glycoprotein ectoenzyme, referring to its catalytic site that is expressed on the external cell surface of many cell types, including macrophages, neutrophils, renal tubular cells, small intestinal epithelial cells, neuronal synaptic membranes, and endometrial stromal cells (25, 26, 27, 43, 44). APN cleaves IL-8 and inactivates its chemotactic activity in vitro (25, 26, 27, 43, 44). APN also inhibits autocrine stimulation of neutrophils by IL-8 (25, 26, 27). In the human endometrium, APN is localized to the perijunctional stroma (i.e. the glandular/stromal interface) by IHC (45).
In our study we observed APN by IHC in the human fallopian tube. The IHC staining pattern localized predominantly in a focal band at the junction of the epithelial and stromal cells, with a distribution similar to that seen in the endometrium. Unlike the endometrium, in the fallopian tube APN is also present in the perivascular stromal tissue. This may represent a control mechanism to limit systemic absorption of IL-8, as IL-8 produced by the tubal epithelial cells would be limited to either the tubal epithelium and/or secretion into the tubal lumen. In this regard, IL-8 has been identified in human fallopian tubal secretions (30). As IL-8 is a chemoattractant for neutrophils, APN in this location may degrade epithelial IL-8 before diffusion into the stromal tissue. Similarly, the perivascular stromal APN may serve as a second barrier against systemic absorption and prevent an influx of neutrophils and proinflammatory effects of IL-8 in the normal tube.
Further studies are warranted to define the role of the IL-8 system in the human fallopian tube. Experiments may evaluate the protein production and secretion both in vivo and in vitro in fallopian tube cells. There is also a need to study the distribution and expression of IL-8 and its receptors in postmenopausal women with and without hormonal replacement therapy and in reproductive-aged women undergoing hormonal treatments. Studies should address the IL-8 system in hydrosalpinges and hydrosalpinx fluid. The role of the IL-8 system in disease states of chlamydial infection and ectopic pregnancy should also be investigated. As IL-8RA and IL-8RB localized to the tubal epithelium, the growth effects of in vitro treatment of epithelial cells with IL-8 should be assessed. Further confirmation of the role of IL-8 may be investigated in vitro and in vivo with regulatory experiments using blocking antibodies, antisense techniques, and receptor homolog gene deletion (knockout) mice.
Received August 24, 2000.
Revised January 19, 2001.
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