Integrative and Comparative Biology Advance Access originally published online on August 30, 2006
Integrative and Comparative Biology 2006 46(6):1082-1087; doi:10.1093/icb/icl036
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Sex hormone modulation of human uterine epithelial cell immune responses
Physiology Department, Dartmouth Medical School One Medical Center Drive, Lebanon, NH 03756, USA
Correspondence: 1E-mail: John.V.Fahey{at}Dartmouth.edu
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Synopsis
IntroductionSexually transmitted infections are a major worldwide public health problem affecting millions of people. A number of bacteria, fungi, viruses, and protozoa can infect reproductive tissues, resulting in varying degrees of pathology ranging from little discomfort to death. The female reproductive tract has evolved innate and adaptive immune mechanisms that protect from microbial infection, thereby reducing infection and disease. Central to this protection are the epithelial cells that line the female reproductive tract. In the uterus, columnar epithelial cells provide a physical barrier to microbial infection, possess toll-like receptors that detect pathogens and secrete a number of constitutive and induced factors that directly or indirectly hinder infection. For example, uterine epithelial cells secrete peptides that destroy pathogenic microbes. In addition, epithelial cells produce chemokines and cytokines that attract and activate innate immune cells and serve as a link to the adaptive immune system. Further, uterine epithelial cells serve as a conduit for secretory antibodies to enter the lumen and can present antigen to T cells. These protective mechanisms contribute to an environment in the uterus that is generally considered sterile, unlike the environment in the lower female reproductive tract. The uterine environment is in constant flux due to the concentration changes in sex hormones that occur in preparation for reproduction. The sex hormones estrogen and progesterone alter the local immune system to prepare for conception, influence how well the immune system will tolerate antigenic sperm and a semi-allogeneic fetus and yet provide a network of protective immune mechanisms against microbial pathogens. Understanding how sex hormones influence uterine epithelial cell function will provide a basis for immune protection in the uterus.
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Introduction |
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More than 20 pathogens are transmissible through sexual intercourse and sexually transmitted infections (STI) have reached epidemic proportions throughout the world. For example, the World Health Organization estimates more than 300 million new infections of Trichomonas vaginalis, Chlamydia trachomatis or Neisseria gonorrhea occur annually throughout the world. Other prevalent STI include Treponema pallidum (syphilis, 12 million infections worldwide annually) and human immunodeficiency virus (HIV); a proportion of the latter's 5 million annual cases will develop AIDS. Some STI can be transmitted vertically to the fetus, resulting in preterm deliveries and/or life-threatening systemic illness in newborn infants. Generally, adolescents and young adults are the demographic age groups most frequently affected with STI, and women are more likely than men to suffer the consequences of these serious infections. Individuals infected with one microorganism are often more susceptible to infection with a second sexually transmitted pathogen. In addition to death, STI can lead to infertility, significant pain, and loss of life quality.
Understanding how the immune system protects against potential pathogens is essential for preventing STI. In the female reproductive tract, recent research has identified a variety of innate and adaptive immune cells and mechanisms that exist to hinder infection by microorganisms (Wira, Fahey and others 2005
). The local immune surveillance and response to pathogens in the female reproductive tract is under the influence of a constantly changing environment orchestrated by sex hormones. Endocrine-induced changes during the menstrual cycle control uterine cell growth and differentiation, as well as the composition and function of immune cells in the uterus.
The human uterus undergoes dynamic changes during the menstrual cycle; these changes are largely driven by the sex steroid hormones estradiol and progesterone. During the proliferative phase, circulating estradiol and locally produced growth factors contribute to vascular growth changes and vasodilation, providing increased oxygen, nutrients and growth factors for the proliferation of epithelial cells. The progesterone dominated secretory phase is characterized by differentiation of epithelial glands and growth and differentiation of stromal fibroblasts. Epithelial–stromal cell interactions are essential in facilitating steroid hormone-induced growth and development in the endometrium (Cooke and others 1997). Throughout these hormone-induced changes, the uterus must prepare for a conceptus, defend against pathogens, and resist attacking a semi-allogeneic fetus. Epithelial cells play a central and necessary role in these events.
Human uterine epithelial cells act as sentinels of protection against potentially pathogenic microorganisms, promote normal reproductive tract physiology including during pregnancy, and play an essential role in regulating immunity to provide for a healthy mother and allogeneic conceptus/fetus. Our goal in this review is to identify the major ways that epithelial cells contribute to immune protection against pathogens in the human uterus, and to outline the extent to which epithelial cell immunity is regulated by sex hormones.
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Barrier function of uterine epithelial cells |
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Human uterine epithelial cells provide a physical barrier to protect against microbial infection. Tight junctions between the columnar epithelial cells maintain the integrity of the mucosal monolayer; disruption of the tight junctions or damage to the epithelial layer can lead to infection, resulting in infertility and potential life-threatening illness. With an apical surface facing the lumen and a basolateral surface to the basement membrane and underlying cells, epithelial cells have a structural and functional polarized orientation. The tight junction barrier prevents the mixing of apical and basolateral contents, and permits the epithelial cells to respond to different stimuli and serve as a directional conduit for different factors. For example, the epithelial cell polymeric immunoglobulin receptor (pIgR) transverses the epithelial cell from the basolateral side to the apical side to release IgA immunoglobulins into the lumen (Wira and Stern 1992
). Similarly, uterine epithelial cells secrete cytokines such as TGFß preferentially at the basolateral surface and TNF
at the apical surface (Grant and Wira 2003). A 10-fold increase in transepithelial resistance, an indicator of tight junction formation and a purified epithelial cell population, is commonly achieved with primary cultures of human uterine cells. Physiological concentrations of estradiol significantly reduce the transepithelial resistance of a human uterine epithelial cell line. This reduction was significantly blocked by pretreatment of the epithelial cells with the estrogen receptor antagonist ICI 182,780, indicating that epithelial monolayer integrity is directly influenced by estrogen via the estrogen receptor. |
Toll-like receptors on uterine epithelial cells |
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Toll-like receptors (TLR) recognize a plethora of specific bacterial, fungal, and viral components; ligand binding to a TLR can result in the activation of signaling pathways and specific transcription factors leading to the induction of pro-inflammatory cytokines and/or microbicides that effectively remove the pathogen (see Takeda and Akira 2005
for review). Human uterine epithelial cell lines express TLR (Schaefer and others 2004; Young and others 2004; Hirata and others 2005; Schaefer and others 2005a). Addition of the TLR2 and TLR5 agonists zymogen and flagellin to the well-differentiated human uterine epithelial cell line ECC-1 stimulated the secretion of the chemokines IL-8 and MCP-1, respectively, as well as the cytokine IL-6. We have also shown that cultured primary human uterine epithelial cells express TLR 1 through 9 indicating the potential to respond to a wide range of potential pathogens (Schaefer and others 2005a). For example, the TLR3 agonist poly (I:C) stimulated the uterine epithelial cells to secrete several pro-inflammatory cytokines and chemokines, suggesting that uterine epithelial cells possess the inherent capability to respond to RNA viruses. Recently, one group of investigators has provided evidence for estrogen regulation of TLR function, as well as variation of TLR during the menstrual cycle (Lesmeister and others 2005; Jorgenson and others 2005). |
Production of microbicides by uterine epithelial cells |
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Since the adaptive immune system at mucosal surfaces may take days to be activated and effective against pathogens, innate protective mechanisms that are inherently immediate are essential for protection against potential pathogens (Wira, Fahey and others 2005
). One such mechanism is the production and/or secretion of factors by epithelial cells that inhibit the growth of microorganisms. Among the epithelial cell secretions with known bactericidal effects are defensins, secretory leukocyte protease inhibitor (SLPI), the enzymes lysozyme and lactoferrin, tracheal antimicrobial peptide, and numerous other small peptides (for review, see Ganz and Lehrer 1995). For example, human defensin-5 was shown with an apical orientation on uterine epithelial cells, suggesting secretion mode (Quayle and others 1998). Human ß-defensin 1 (HBD1) expression has been shown in situ (Valore and others 1998), and in cultured epithelial cells (King and others 2002; Schaefer and others 2005a). Using real-time quantitative RT–PCR of endometrial epithelium, King and associates have shown that HBD3 mRNA expression is highest during the secretory phase of the menstrual cycle while HBD4 mRNA levels peak in the proliferative phase (King, Fleming and others 2003). We found that TLR3 stimulation of uterine epithelial cells induces the mRNA expression of the antimicrobial peptides HBD1 and HBD2 (Schaefer and others 2005a; Schaefer, Wright and others 2005), and that estrogen inhibits the induced expression of HBD2 (Schaefer, Wright and others 2005). In other studies, the TLR3-mediated stimulation with poly (I:C) of uterine epithelial cells induced the mRNA expression of IFNß and IFNß-stimulated antiviral genes.
Apical secretions from polarized epithelial cells recovered from women at the proliferative and secretory stages of the menstrual cycle, but not from postmenopausal women, were equally effective in killing Staphylococcus aureus and Escherichia coli (Fahey and Wira 2002). SLPI production correlated with bactericidal activity with respect to menstrual status and time in culture, and anti-SLPI antibody significantly decreased bactericidal activity from premenopausal epithelial cell rinses. These studies extend the findings of others showing that expression of SLPI varies in cervical mucus during the menstrual cycle, increases in amniotic fluid during gestation and labor (Denison and others 1999), and is released by cervical tissue in response to progesterone (King, Morgan and others 2003). The primary site of SLPI synthesis in the endometrium and decidua was the glandular epithelium, and tissues derived from women in late secretory phase secreted more SLPI than tissues obtained from women in the proliferative phase (King and others 2000; Fleming and others 2003). The expression of endometrial SLPI was upregulated by estrogen in the rat (Chen and others 2004), and by progesterone in the Rhesus monkey (Ace and Okulicz 2004) and human (King, Morgan and others 2003). We recently demonstrated that estrogen stimulates the secretion of SLPI by human uterine epithelial cells. There is a correlation between SLPI induction and the time of receptivity and/or implantation. Taken together, these findings suggest that sex hormones play a regulatory role in innate immune protection. The benefit of SLPI expression at such critical times could include its antibiotic action, as well as its anti-inflammatory effects of inhibiting elastase and NF-kappaB. The latter is required for the production of pro-inflammatory chemokines and cytokines in response to microbial antigens. It has been suggested that one reason that the endometrium maintains a predominantly sterile environment is due to the production of antimicrobial factors (Quayle 2002; Wira, Grant-Tschudy and others 2005).
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Chemokine and cytokine production by uterine epithelial cells |
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The endometrium is characterized by progressive tissue growth and remodeling which occurs during each menstrual cycle and the sloughing off of the outer two-thirds of the uterine mucosa during menses. Cell proliferation, apoptosis, and cell migration are essential for reproductive tract renewal to occur. Growth in preparation for fertilization, implantation, and successful pregnancy is mediated by a changing pattern of cytokine and adhesion molecule expression that is regulated by the sex steroid hormones (Tabibzadeh 1990
; Tabibzadeh 1996; Dominguez and others 2002). Kayisli and associates reported on the importance of IL-8 and MCP-1 in normal uterine physiology, particularly in proliferation, angiogenesis, menstruation, implantation, cervical ripening, and parturition (Kayisli and others 2002). The chemokines and cytokines regulate production of themselves and other chemokines/cytokines by autocrine and paracrine mechanisms. Also, sex hormones exert control over many chemokines/cytokines in the female reproductive tract. For example, progesterone withdrawal results in upregulation of MCP-1 and IL-8, leading to chemotaxis and activation of monocytes and neutrophils, which results in release and activation of matrix metalloproteinases for initiation of menstruation (Critchley and others 2001). Thus, concentrations of chemokines and cytokines will vary in the endometrium during normal physiological processes, as well as pathological conditions, such as infection and endometriosis.
We have demonstrated the constitutive and induced secretion of the chemokines IL-8, MCP-1, MIP-1ß, and the cytokines IL-6, TNF, G-CSF, GM-CSF, and MIF by uterine epithelial cell lines and primary cells (Schaefer and others 2004; Fahey and others 2005; Schaefer and others 2005b). The secreted pro-inflammatory mediators attract and stimulate the immune cells, often provoking further inflammation. For example, the chemokines IL-8, MCP-1, and MIP-1ß are chemoattractants for neutrophils, monocytes, and T cells, respectively. In response to the cytokines TNF, IL-6, GM-CSF, and G-CSF, the immune cells upregulate the secretion of these and other pro-inflammatory cytokines, and induce differentiation of leukocytes to a more functionally active cell, such as phagocytosis for macrophages or antigen presentation for dendritic cells. Some epithelial secreted factors have multiple effects in innate and adaptive immunity. For example, the microbicide HBD2, which we have shown is produced by primary polarized uterine epithelial cells in culture (Schaefer and others 2005a), acts also as a chemokine for the recruitment of memory T cells and immature dendritic cells (Yang and others 1999) and neutrophils (Niyonsaba and others 2004). Similarly, the chemokine MIP-3, which is secreted by uterine epithelial cells in response to LPS (Crane-Godreau and Wira 2004; Crane-Godreau and Wira 2005), has also been shown to be microbicidal for bacteria (Hoover and others 2002). These epithelial factors, which are modulated by sex hormones, undoubtedly contribute to the resident and temporary populations of immune cells in the subepithelial layers of the endometrium. For example, the chemokines produced by the epithelial cells could account for the influx of leukocytes and lymphocytes that form lymphoid aggregates observed during the secretory phase of normal endometrium (Yeaman and others 1997). The immune cells, also under hormonal control, participate in architectural changes that occur during the menstrual cycle, as well as formation of the trophoblast in the presence of a conceptus.
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Regulation of immunoglobulin secretion into the lumen by uterine epithelial cells |
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At mucosal surfaces, pIgR is responsible for transporting polymeric IgA across epithelial cells. The female sex hormones estradiol and progesterone have profound effects on the local production and immunoglobulin transport in the rodent (Wira and Sandoe 1987
; Richardson and others 1993) and human reproductive tracts (Menge and Mestecky 1993). When cultured human endometrial cells are incubated with IL-4 and IFN
, it has been demonstrated that the presence of estrogen increases the expression of pIgR, thereby increasing the transport of IgA into the lumen (Menge and Mestecky 1993). We showed that normal epithelial cells from the female reproductive tract produced secretory component, the external domain of the pIgR, and that secretory component produced by uterine epithelial cells accumulated preferentially in the apical compartment and correlated with increased transepithelial resistance (Fahey and others 1998). These results suggest that uterine epithelial cells play a key regulatory role in the control of IgA transcytosis from tissue into secretions. |
Antigen presentation by uterine epithelial cells |
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Antigen presentation involves the internalization and processing of exogenous antigen to immunogenic fragments that are then presented in combination with either MHC class I or class II molecules to T lymphocytes. We examined mixed cell suspensions from throughout the reproductive tract and found that they contained cells capable of presenting foreign antigen to autologous T cells (Fahey and others 1999
). To more fully characterize the immune system in the human female reproductive tract, uterine epithelial and stromal cells from hysterectomy patients were purified to assess the capacity of these cells to present antigen. Irradiated epithelial cells cocultured with T cells and tetanus toxoid induced syngeneic T cell proliferation in comparison to cultures without tetanus toxoid (Wallace and others 2001; Fahey and others 2006). Proliferation was significant, indicating that both purified epithelial cells and stromal cells were capable of antigen presentation to autologous T cells. The purified epithelial cells express MHC class II, as well as the co-stimulatory receptors CD40 and CD1d (Fahey and others 2006), indicating the potential for antigen presentation. The effect of menstrual status/sex steroids on antigen presentation by human uterine epithelial cells is under investigation. In the mouse, we have demonstrated that uterine epithelial cells present antigen and that estrogen inhibits antigen presentation. |
Summary |
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In conclusion, these studies over the past 10–15 years demonstrate the central role of epithelial cells in immune protection. While emphasis in this presentation has focused on uterine epithelial cells, studies by a number of laboratories including ours, demonstrate that the epithelial lining of the fallopian tube, uterus, cervix, and vagina function as a first line of defense against potential pathogens to which they are periodically exposed. What is yet to be fully appreciated is the dynamic balance of immune protection versus reproductive potential that must be maintained for reproductive health and perpetuation of the species. Recognition that sex hormones modulate both events, when coupled with the dynamic balance between innate and adaptive immunity, provides insight into evolutionary success.
Conflict of interest: None declared.
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Footnotes |
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From the symposium "Ecological Immunology: Recent Advances and Applications for Conservation and Public Health" presented at the annual meeting of the Society for Integrative and Comparative Biology.
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