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The Queen's Medical Research Institute, Reproductive and Developmental Sciences, Centre for Reproductive Biology, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
Correspondence should be addressed to A E King; Email: anne.king{at}ed.ac.uk
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Abstract |
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 Top Abstract IntroductionNatural antimicrobial peptides...Disorders of the female...ConclusionAcknowledgementsReferences |
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Introduction |
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TopAbstractIntroductionNatural antimicrobial peptides...Disorders of the female...ConclusionAcknowledgementsReferences |
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B (NFKB) dependent (and independent) pathways to induce chemokine and cytokine expression that activate a range of host responses (Zarember & Godowski 2002). A summary of the cellular origin, target cell lineages and function of each family of molecules is shown in Fig. 1. The role of macrophages, dendritic, myeloid, natural killer cells and neutrophils in the innate immune system are outwith the scope of this review and have been recently discussed in detail elsewhere (Wira et al. 2005). Similarly, this review focuses specifically on data from human studies, except where individual animal work was thought to be especially relevant.
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Natural antimicrobial peptides (NAPs) |
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SLPI and elafin are expressed throughout the female genital tract (King et al. 2000, 2003c; see Table 1). SLPI and elafin expression has been demonstrated in the vagina (Draper et al. 2000) and cervix, with high concentrations of SLPI demonstrated in the cervical mucus (Helmig et al. 1995, Pfundt et al. 1996). We have shown that endocervical and vaginal cell lines express both SLPI and elafin, and that expression in endocervical cells is increased by treatment with the bacterial wall product lipopolysaccharide (SJ Stock, unpublished observations). Neutrophils within the human endometrium area particularly rich source of elafin during menstruation (see Fig. 4), whereas the endometrial epithelium expresses SLPI during the progesterone-dominant secretory phase of the cycle (King et al. 2000, 2003c). In vitro studies of polarized endometrial epithelial cells have shown that the presence of an anti-SLPI antibody reduces the antibacterial activity of secretions from the apical surface of these cells (Fahey & Wira 2002). These functional data suggest that SLPI is involved in the endometrial innate immune response at least in vitro. In common with the rest of the female reproductive tract, the Fallopian tube morphology undergoes cyclical changes under the influence of oestrogen and progesterone (Sulz et al. 1998), and while SLPI and elafin expression have been localized to the Fallopian tube epithelium (Ota et al. 2002, Horne et al. unpublished data) their temporal expression profiles have not been detailed.
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SLPI and elafin demonstrate a variety of anti-inflammatory effects in a number of other tissues, which cannot be solely attributed to their anti-proteinase or anti-bacterial activities. In an animal model of chemically induced lung fibrosis, administration of SLPI decreases tissue damage, and even a truncated form that lacks the anti-elastase domain exerts this effect (Mitsuhashi et al. 1996). SLPI also decreases cortical damage after ischaemic-induced stroke in rats (Wang et al. 2003). Forced expression of elafin in animal models modulates the systemic and pulmonary response to lipopolysaccharide (LPS; Sallenave et al. 2003) and reduces inflammation associated with myocardial infarction (Ohta et al. 2004). In humans, SLPI and elafin induction appear attenuated in Crohn's disease, characterized by inflammation affecting the full thickness of intestinal wall, when compared with ulcerative colitis, which is an inflammatory condition only involving the mucosa (Schmid et al. 2007). Some of the anti-inflammatory effects of the anti-leukoproteinases may involve inhibition of NFKB. In vitro, overexpression of SLPI suppresses NFKB activation (Jin et al. 1997, Sano et al. 2003, Henriksen et al. 2004). It can prevent proteosome-dependent IBβ degradation (Lentsch et al. 1999) and also directly bind to NFKB consensus sites on DNA, inhibiting transcription (Taggart et al. 2005). Wound healing and tissue remodelling are other processes involving the anti-leukoproteinases. SLPI and elafin are produced in response to cutaneous injury (van Bergen et al. 1996, Wingens et al. 1998) and SLPI null mice show impaired cutaneous wound healing and increased inflammation and elastase activity (Ashcroft et al. 2000, Angelov et al. 2004). SLPI can also modulate production of matrix metalloproteinases from monocytes by inhibiting enzymes involved in PGE2 (prostaglandin E2) synthesis (Zhang et al. 1997).
Defensins
Leukocytes and epithelial cells are the main sources of human defensins (Klotman & Chang 2006). Human β-defensins (HBD) 1–4 and 
-defensin (human defensin 5, HD5) have all been reported to be expressed in the endometrial epithelium, each with their own unique temporal expression profile (Svinarich et al. 1997, Quayle et al. 1998, Valore et al. 1998, Fleming et al. 2003, King et al. 2003a,b). HBD1, HBD3 and HD5 are expressed at highest levels during the secretory phase (Quayle et al. 1998, Fleming et al. 2003, King et al. 2003b; see Table 1). By contrast, HBD2 mRNA expression shows a dramatic peak during menstruation while HBD4 is expressed mainly in the proliferative phase (Fleming et al. 2003, King et al. 2003b). The functional implications of these different patterns of expression have not been determined and may relate to differences in antimicrobial activity of members of the defensin family or to their other activities such as regulation of leukocyte chemotaxis. HD5 has also been demonstrated in the vagina, cervix and Fallopian tube (Quayle et al. 1998). HBD2 is also present in cervicovaginal secretions and is expressed by a vaginal keratinocyte cell line in vitro (SJ Stock, unpublished observations). HBD1–3 are widely expressed in the pregnant uterus with expression in the amnion, decidua, chorion and placental trophoblast (King et al. 2007, Stock et al. 2007). Their presence at key sites suggests that they are likely to be involved in the innate immune response during pregnancy and may act to prevent uterine infection (see Table 1).
Toll-like receptors (TLRs)
TLRs 1–10 are expressed in the female reproductive tract (Darville et al. 2003, Pioli et al. 2004, Aflatoonian et al. 2007). Vaginal epithelial cell lines have been shown to express TLR1–3, TLR5 and TLR6, and primary endocervical epithelial cells have been shown to express TLR1–3 and TLR6 (Fichorova et al. 2002). Endometrial epithelial cell lines, primary endometrial epithelial cells and primary decidual cell cultures express TLR1–9, indicating the potential to respond to a wide range of pathogens (Schaefer et al. 2004, 2005, Krikun et al. 2007). TLRs are present in both endometrial epithelial and stromal cells (Aflatoonian et al. 2007, Hirata et al. 2007) and have also been reported in uterine NK cells, an endometrial cell with a key role in implantation and early pregnancy (Eriksson et al. 2006).
The TLRs are differentially expressed in each individual reproductive tract tissue and also show cycle-dependent expression in the endometrium. For example, TLR2 and TLR4 show higher expression in the Fallopian tube and endometrium compared with that in the cervix (Pioli et al. 2004). Studies detailing cycle-dependent expression in endometrium are contradictory with one study suggesting that TLR2–4 and TLR9 mRNA expression is higher during the perimenstrual phase (Hirata et al. 2007), while another shows peak expression of TLR2–6, TLR9 and TLR10 mRNA in the secretory phase (Aflatoonian et al. 2007). However, there are differences in the cycle phases compared in these studies and also in the way that menstrual cycle phase was confirmed.
TLRs have been shown to be functional in cell types from throughout the reproductive tract in in vitro experiments. Endometrial, cervical and Fallopian tube epithelial cells have both been shown to respond to the TLR3 ligand, poly I:C, with increased cytokine output (Lesmeister et al. 2005, Andersen et al. 2006, Ghosh et al. 2008, Nasu et al. 2007). Fallopian tube fibroblasts and endometrial epithelial and stromal cells have been shown to increase inflammatory mediator output in response to LPS (lipopolysaccharide), a TLR4 ligand (Hirata et al. 2005, Itoh et al. 2006). These in vitro data suggest that TLRs on reproductive tract cells will be capable of responding to pathogen products in vivo.
TLRs are also present in the pregnant uterus. Several studies have examined TLR expression both in the first trimester and in late pregnancy. TLR2 and TLR4 are widely reported to be present on trophoblast cells (Holmlund et al. 2002, Abrahams et al. 2004, Kumazaki et al. 2004, Beijar et al. 2006, Ma et al. 2007). The related, intracellular innate immune receptors nucleotide oligomerization domain (NOD) 1 and 2 are also present in the first trimester trophoblast (Costello et al. 2007). In vitro studies with the first trimester trophoblast have shown TLR3 and TLR4 to respond to their ligands by increasing cytokine and chemokine output and increasing chemotaxis of monocytes and neutrophils (Abrahams et al. 2004, 2005, 2006). Similar studies have shown TLRs on syncytiotrophoblast and in villous explants from term pregnancies to signal responses to ligand binding (Holmlund et al. 2002, Ma et al. 2007). These studies suggest that the trophoblast is capable of mounting an innate immune response and may also initiate activation of the adaptive immune response.
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Disorders of the female reproductive tract |
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and MIP2 (macrophage inflammatory protein), in genital tract secretions and reduced chronic pathology in the Fallopian tube relative to normal mice, although the progression of infection does not differ (Darville et al. 2003). This suggests that, at least in the mouse, TLR2 plays a central role in Fallopian tube pathology as a result of chlamydial infection. Mice deficient in TLR4 did not show changes relative to the wild type. Studies in mice also suggest that NOD1 does not play a major role in the genital tract response to chlamydial infection. While the presence of a dominant negative mutant of NOD1 partially inhibited NFKB activation as a result of chlamydial infection of the cervical epithelial HeLa cell line, proinflammatory mediator expression in the genital tracts of NOD1-deficient mice after chlamydial infection was comparable with that in wild-type mice (Welter-Stahl et al. 2006). However, these data may not be representative of infection with C. trachomatis as the pathology of infection has been reported to differ between C. muridarum and C. trachomatis (Morre et al. 2000). There are few studies examining the role of TLRs in the infection of human cells with C. trachomatis and these have yielded conflicting information depending on the cell type examined. However, there is evidence to suggest that TLR2 and TLR4 may both be involved in the response to Chlamydia. O'Connell et al. (2006) have reported that TLR2 is recruited to intracellular Chlamydiae in HEK293 cells transfected with TLR2 and that TLR2 is required for cellular activation (determined by IL-8 measurement) during infection. In human microvascular cells, chlamydial heat shock protein 60 (HSP60) acts via TLR4 to activate NFKB and increase IL-8 secretion (Bulut et al. 2002).
The role of TLRs and NODs expressed by cells of the female reproductive tract (e.g. Fallopian tube epithelium) in the response to chlamydial infection, or any STI, remains poorly understood. However, the aforementioned differences in the expression pattern of the TLRs in individual reproductive tract microenvironments suggest they may contribute, at least in part, to a compartmentalized immune response towards pathogen invasion (Pioli et al. 2004). Furthermore, a recent study examining single nucleotide polymorphisms in TLR9, TLR4, CD14 and NOD2 in women with chlamydial infections indicated that women with SNPs in two or more of these genes have a trend towards an increased risk of tubal pathology (den Hartog et al. 2006) suggesting that pattern recognition receptors are involved in the progression of the infection.
Tubal damage, infertility and tubal ectopic pregnancy
Although it has been suggested that chlamydial infection is one of the major causes of tubal damage (Odland et al. 1993), the innate immunopathogenic events that lead to infertility and tubal ectopic pregnancy following infection are unclear (see Table 2). In vitro studies have demonstrated that Chlamydia induces expression of SLPI in HeLa and a human trophoblast cell line (N Wheelhouse, personal communication). It is possible that Chlamydia acts via NFKB by way of the above signalling cascade, and that persistent, or repeated, infection causes atypical expression of SLPI in the uterus and Fallopian tube leading to tubal damage, and/or blockage, or to a susceptibility to tubal implantation. To our knowledge, there have been no studies performed examining the expression pattern of NAPs or TLRs in these pathologies.
With tubal ectopic pregnancy, direct comparison of the expression of factors important for innate immunity between tubal and intrauterine sites is difficult due to the anatomical differences of the two implantation locations. However, similar to the endometrial response to an intrauterine pregnancy, with a tubal gestation, there is a decidual reaction in the uterine cavity but not usually in the Fallopian tube (Stock 1991). The uterine decidua contains innate immune leukocytes, such as CD56+ uterine natural killer cells, macrophages and mast cells (Bulmer et al. 1988, King & Loke 1991, Clark et al. 1994, Hunt 1994, Marx et al. 1999). We therefore compared SLPI and elafin expression in the uterine decidua of women with ongoing intrauterine (women undergoing surgical termination of pregnancy), failed intrauterine (women with miscarriage) and tubal gestations and demonstrated that SLPI (but not elafin) mRNA expression was significantly higher in the uterine decidua of women with a tubal compared with a failed intrauterine gestation (miscarriage; Dalgetty et al. 2008). If the uterine environment truly reflects that of the Fallopian tube, the abnormal expression of SLPI in the uterine decidua may simply mirror the biological changes occurring in the Fallopian tube due to extra-uterine implantation. Alternatively, the abnormal expression of SLPI may predispose to, rather than be a consequence of, tubal pregnancy.
Preterm birth
There is evidence to suggest that expression of natural antimicrobials is altered in preterm labour, particularly in cases of chorioamnionitis (see Table 2). HBD3 protein (Buhimschi et al. 2004) and elafin mRNA and protein expression (Tromp et al. 2004) have both been reported to increase in the fetal membranes of pregnancies complicated with chorioamnionitis suggesting that these natural antimicrobials are upregulated as a result of infection. In addition, amniotic fluid concentrations of SLPI (Helmig et al. 2002) and mRNA and protein expression of elafin in fetal membranes (Tromp et al. 2004) are reduced in cases of preterm premature rupture of membranes. This reduced expression may result in decreased anti-protease activity promoting a shift in favour of protease-mediated degradation of membranes. Their reduced expression may, however, also reduce antimicrobial protection in the uterus, allowing the establishment of detrimental infections. It should be noted that the studies detailed above do not address whether the changes described are a cause or effect of the pathology and there are no functional data showing a role for natural antimicrobials in preterm labour.
Studies in mice suggest that activation of TLRs results in preterm labour. Administration of heat-killed Escherichia coli to TLR-normal pregnant mice results in preterm labour, while identical treatment of TLR4-mutant mice has a reduced effect. In this study, TLR4 stimulation reduced prostaglandin dehydrogenase expression in fetal membranes and myometrium resulting in increased local concentrations of prostaglandins; mediators with a well-established role in the onset of labour (Wang & Hirsch 2003). Preterm delivery also occurs in mice upon activation of TLR2 or TLR3 (Ilievski et al. 2007) with TLR3 activation resulting in increased levels of CCL5 and IFN
in uterine tissues. Zhang et al. (2007) have reported pregnancy failure and abnormal uterine spiral artery development in mice as a result of administration of the TLR3 agonist, poly I:C, earlier in gestation. These studies suggest that the presence of TLR ligands in the uterus stimulate local inflammatory pathways resulting in preterm labour.
Studies in human pregnancies also suggest that TLRs may be involved in the onset of preterm labour associated with infection. It has been reported that TLR2 and TLR4 protein expression is altered in pregnancies complicated with chorioamnionitis (inflammation between the amnion and the chorion). TLR2 expression is reported to be reduced in placentae affected by chorioamnionitis (Rindsjo et al. 2007), while it is increased in chorioamnion (Kim et al. 2004). TLR4 expression in placental macrophages (Hofbauer cells) is also reported to increase in preterm delivery complicated with chorioamnionitis (Kumazaki et al. 2004). While these studies suggest that TLR expression changes with chorioamnionitis, it remains unclear whether this is a cause or effect of inflammation and/or parturition. Additionally, changes in expression may not be reflected in functional activity of the TLRs although some studies have suggested that there may be an association between TLR function and pregnancy failure or preterm labour. The chlamydial HSP60 has been shown to cause apoptosis of primary first trimester trophoblast cells, placental fibroblasts and the JEG3 trophoblast cell line via TLR4 (Equils et al. 2006). It has been suggested that TLR4 activity may cause placental apoptosis and possibly compromise a pregnancy in women with chlamydial infection. In addition, Lorenz et al. (2002) have reported that when an Asp299Gly polymorphism is present in the TLR4 gene of infants they have a higher risk of preterm birth. This polymorphism causes impaired receptor function suggesting that a reduced response to gram-negative bacteria increases the likelihood of infection and subsequent preterm labour. It has also been reported that infants carrying two copies of a variant TLR2 gene are at increased risk of premature delivery (Krediet et al. 2007).
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Conclusion |
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TopAbstractIntroductionNatural antimicrobial peptides...Disorders of the female...ConclusionAcknowledgementsReferences |
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The study of the innate immune response has highlighted the importance of host-related factors in the response to infectious agents. Genetic variation in innate immunity can explain individual differences in responses to infection. A suboptimal innate immune response may result in a permissive environment for pathogen colonization, whereas an over-exuberant response will cause excessive inflammation and tissue damage. This may be why a ‘one-size fits all’ approach has been hitherto unsuccessful and modulation of the host response to infection is an attractive alternative or adjuvant approach to antibiotic therapies in treatment of genital tract infections. TLR agonists and antagonists are currently under clinical development for the treatment of cancer, allergies and as vaccines and vaccine adjuvants (Kanzler et al. 2007) raising the possibility that in the future interventions may be aimed at modulating the innate immune response in the reproductive tract. Further research into the innate immune response may elucidate pathological mechanisms underlying infectious morbidities such as tubal infertility and preterm labour, but as yet few studies have examined the functional effects of innate immune components such as NAPs and TLRs in the reproductive tract. While existing SLPI (Ashcroft et al. 2000) and TLR-null (Sugawara et al. 2003, Andersen-Nissen et al. 2007) mutant mouse models show impaired wound healing and altered responses to infection, they have provided little information relating directly to the reproductive tract. In addition, fundamental differences in key physiological reproductive processes, such as implantation and placentation, exist between mouse and human limiting the relevance of these rodent models.
It is anticipated that a greater understanding of the function of the innate immune system in the reproductive tract and the development of TLR agonists and antagonists for clinical use may lead to advances in the management of clinically important conditions, such as tubal infertility, ectopic pregnancy and preterm labour.
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Acknowledgements |
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TopAbstractIntroductionNatural antimicrobial peptides...Disorders of the female...ConclusionAcknowledgementsReferences |
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Received 17 December 2007
First decision 26 February 2008
Revised manuscript received 18 January 2008
Accepted 14 March 2008
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TopAbstractIntroductionNatural antimicrobial peptides...Disorders of the female...ConclusionAcknowledgementsReferences |
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