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Keywords:

  • Cytokines;
  • human;
  • parturition;
  • preterm;
  • toll-like receptors

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cytokines and labour
  5. Toll-like receptors
  6. TLRs at the maternal-fetal interface
  7. Mechanisms of action of TLR
  8. TLR signalling pathways
  9. TLR and term and PTL
  10. Clinical perspective
  11. Summary
  12. References

Toll-like receptors (TLR) have emerged as key upstream mediators of inflammation at many tissue sites in humans. Inflammatory processes are involved in the process of parturition suggesting that TLR activity within gestation-associated tissues might have an important role in the initiation and/or maintenance of normal term labour and in various pathological states of pregnancy such as infection-associated preterm labour. Either TLRs or their signalling molecules might be excellent therapeutic targets for prevention of preterm labour.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cytokines and labour
  5. Toll-like receptors
  6. TLRs at the maternal-fetal interface
  7. Mechanisms of action of TLR
  8. TLR signalling pathways
  9. TLR and term and PTL
  10. Clinical perspective
  11. Summary
  12. References

The precise mechanism of the onset of parturition remains unknown. Hypothalamic-pituitary axis activation and progesterone withdrawal at term as elaborated in a sheep model do not seem to explain entirely the events around labour in humans.1 Understanding the onset of labour is of importance in managing cases of failed induction and as an insight into the pathogenesis of preterm labour (PTL), which continues to be an important cause of perinatal mortality and morbidity.2 Studies in humans have focused on the role of cytokines and prostaglandins in the initiation and maintenance of labour.3,4 In particular, the inflammatory response to microbes and endogenous agents by extraembryonic tissues is postulated to play a prominent role in premature labour and normal term labour, respectively. The molecular events leading to cellular recognition of and the response to various microbial products and endogenous agents in PTL and term labour are still unknown.

Cytokines and labour

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cytokines and labour
  5. Toll-like receptors
  6. TLRs at the maternal-fetal interface
  7. Mechanisms of action of TLR
  8. TLR signalling pathways
  9. TLR and term and PTL
  10. Clinical perspective
  11. Summary
  12. References

Cytokines (and chemokines) are small proteins that function in the extracellular environment to facilitate communication between many cell types through their interaction with specific receptors expressed on target cells. They can have autocrine, paracrine or endocrine activity and include key immunological/inflammatory mediators, such as tumour necrosis factor (TNF)-α, interleukin-6 (IL-6) and IL-8. The cellular events that occur at the time of human labour and delivery have been compared with those characteristic of an inflammatory response, and this analogy is highlighted in infection-associated PTL.3–5

The process of labour involves at least three physiologically interdependent processes: remodelling of the cervix to allow it to stretch open to the width of the reproductive tract, weakening and rupture of the membranes in the region that overlies the cervix and the initiation of rhythmic contractions of increasing amplitude and frequency that ultimately force the fetus and placenta from the uterus. Many of these processes are mediated by the immediate action of proinflammatory cytokines or by their downstream effects on prostaglandins and tissue proteinases (Figure 1). Such dramatic upregulation of proinflammatory cytokines is likely to activate novel labour-associated cascades and/or disrupt the delicate balance created by various mechanisms of maternal-fetal tolerance/immune privilege that support pregnancy success.6,7 Induction of strong proinflammatory activity during labour might also help remove placental fragments and prepare the uterus for the pathogens that it will undoubtedly encounter during the immediate postpartum period.

image

Figure 1. Various stimuli (such as microbial stimuli or those related to stress such as heat shock proteins) might initiate similar cascades through their ability to interact with TLRs. Triggering TLRs mediates cytokine release that leads to recruitment of inflammatory cells and increased levels/activity of inflammatory mediators resulting in ripening of the cervix, myometrial contractions and rupture of the fetal membranes. Inhibitors of some of these events in the cascade are known (shown on the right hand side) and these might serve to dampen and/or abrogate the inflammatory cascade. TIMP, tissue inhibitor of metalloproteinase.

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Cervical ripening

Early in labour, IL-8, IL-1β, IL-6 and TNF-α production increase in the human cervix to facilitate cervical ripening and the progression of labour.8 IL-1β and TNF-α increase the production of matrix metalloproteinases (MMP) and cathepsins, and IL-1β downregulates the expression of tissue inhibitor of metalloproteinase, an endogenous inhibitor of MMP.9 A shift in the balance towards proteinase activity favours digestion of collagen and elastin fibres in the extracellular matrix of the cervix to further increase cervical compliance. IL-1β also increases the production of cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2), the most effective chemical for inducing cervical dilation in women. IL-1α, which uses the same receptor as IL-1β, has been shown experimentally to increase COX-2 and PGE2 production by rabbit cervical smooth muscle cells.10 PGE2 might further stimulate labour by increasing the production of proteinases or might play an indirect role by increasing the permeability of blood vessels for leucocyte trafficking.11

Membrane rupture

A similar proinflammatory process takes place in the fetal membranes—the production of IL-8, TNF-α, IL-6 and IL-1β increases in the membranes with preterm and term labour,12–15 and this is associated with an increase in the production of prostaglandins and MMP, such as MMP8 (neutrophil collagenase).16 Sources of cytokines include infiltrating leucocytes, which occur at a greater density in the zone of altered morphology that overlies the cervix,17 cells of the maternal decidua and fetal amniochorion, such as decidual stromal cells and amnion epithelial cells. The portion of the fetal membranes overlying the cervix is likely to have a critical role in membrane rupture, but the cytokine-mediated paracrine interaction between the fetal membranes and myometrium contributes to myometrial contractions.17,18

Myometrial contractions

The pattern of cytokine-related changes described above also occurs in the myometrium where increased protein and/or messenger RNA (mRNA) levels of IL-1β, TNF-α and IL-6 are associated with labour.8,13 IL-1β and TNF-α increase the production of PGE2 and COX-2 by the myometrium.19,20 Similarly, oxytocin upregulates COX-2 and PGE2 production by myometrial cells. Oxytocin and PGE2 increase intracellular calcium concentrations in myometrial cells, as required for uterine contractions.21 IL-6 is postulated to have a role in labour by increasing the expression of oxytocin receptors on myometrial cells and, like IL-1β, increasing oxytocin secretion by myometrial cells.22,23

Cytokine production thus increases several fold at the maternal-fetal interface in association with labour. The challenge is to identify the mechanisms whereby production of these mediators is increased and, for human parturition, to ascertain if upregulated levels and/or activity of these mediators are a cause of labour or simply an effect. Recently, Toll-like receptor (TLR) mediated signalling pathways active in cells of the innate and adaptive immune response (e.g. macrophages and dendritic cells) and leading to the kind of inflammatory cytokine outputs that characterise labour have become a focus of investigation. Consequently, there is much interest in the possibility that TLRs expressed by various gestation-associated tissues might have a pivotal role in the production of key inflammatory mediators associated with the initiation and/or maintenance of labour particularly that triggered prematurely by microbial infection.

Toll-like receptors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cytokines and labour
  5. Toll-like receptors
  6. TLRs at the maternal-fetal interface
  7. Mechanisms of action of TLR
  8. TLR signalling pathways
  9. TLR and term and PTL
  10. Clinical perspective
  11. Summary
  12. References

TLRs have emerged as key upstream mediators of inflammation at many tissue sites in humans and in other organisms. TLRs are a family of proteins, consisting of ten type 1 transmembrane receptor proteins in humans. An 11th family member (TLR11), which is active in mice in response to uropathogenic bacteria has been described as not functional in humans.24

Toll’, derived from the German for ‘amazing’ or ‘mad’, was first discovered in the fruit fly Drosophila melanogaster as a plasma membrane protein with a role in development of dorsoventral polarity during embryogenesis.25 Later, Toll also was found to have a role in the fly’s immunity to fungal infections.26 The first mammalian TLR4, so called because of its sequence homology to the D. melanogaster gene Toll was identified in 1997.27

The TLR family is the best characterised class of mammalian pattern recognition receptors (PRRs). The pattern recognition strategy of these receptors is based upon the detection of a limited set of conserved molecular patterns that are unique to the microbial world. The targets of pattern recognition, sometimes called pathogen-associated molecular patterns (PAMPs), signal to the host the presence of infection.28 Note that PAMPs are also termed microbial-associated molecular patterns, which highlights that not all microbial agents are pathogenic, and danger-associated molecular patterns to highlight that the ligands that can activate the innate immune response are not all microbial in origin but can be produced endogenously (i.e. by the host), typically in response to danger (e.g. cell damage in response to heat stress). TLRs are expressed by cells involved in innate immunity and enable recognition of invading microbes and initiation of antimicrobial activity. While TLRs are now recognised to play a crucial role in the regulation of immune responses, the factors that regulate TLR expression and function are poorly understood.

The strong association between intrauterine infections and fertility problems as well as certain pregnancy complications such as infection-associated PTL indicate that innate immune responses within the female reproductive tract/gestation-associated tissues might have a significant impact on implantation, the success of pregnancy and mechanisms of labour. It is the potential contribution of TLRs expressed by various gestation-associated tissues to the initiation and/or maintenance of labour that forms the focus of this review.

TLRs at the maternal-fetal interface

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cytokines and labour
  5. Toll-like receptors
  6. TLRs at the maternal-fetal interface
  7. Mechanisms of action of TLR
  8. TLR signalling pathways
  9. TLR and term and PTL
  10. Clinical perspective
  11. Summary
  12. References

There is a wealth of literature supporting the production of cytokines by gestation-associated tissues in response to preterm and term labour, intrauterine infection or ex vivo stimulation with microbial products, such as lipopolysaccharide (LPS). As TLRs have been found to link microbial ligands and the production of various inflammatory mediators, it has been postulated that TLRs provide a mechanism of cytokine production at the maternal-fetal interface. Below, TLR expression and activity within each gestation-associated tissue is reviewed. The study of these is in its infancy, and the next few years should see clarification of a more extensive array of TLR-mediated mechanisms in gestation-associated tissues under various reproductive circumstances.

Cervix

As discussed above the cervix undergoes dramatic remodelling during parturition with numerous inflammatory mediators implicated in this. To date, only one study has been published, in which the gene expression of TLRs in the cervix after vaginal delivery or elective caesarean section was determined. The microarrays used in this analysis covered approximately 47 000 probe sets including ones for TLR2, TLR3, TLR4 and TLR5 and showed a significant decrease in expression of transcripts for TLR3 and TLR5 that could be confirmed by conventional quantitative polymerase chain reaction (the apparent upregulation of TLR2 and TLR4 in the microarray study could not be confirmed).29 The biological significance of this remains to be determined but could reflect a direct role for TLR3 and TLR5 in labour via perhaps as yet unidentified endogenous ligands or downregulation of these two receptors by any of the inflammatory mediators upregulated in the cervix at this time.

Placenta

The placenta constitutes a physical and immunological barrier against invading infectious agents and has been called a pregnancy-specific component of the innate immune system. Studies of TLR expression and function at the maternal-fetal interface are limited. Transcripts for TLRs 1–10 have been detected in the human placenta,30–32 as well as in the choriocarcinoma cell lines JAR and BeWo.33 Immunohistochemical studies have shown TLR2 and/or TLR4 expression on trophoblast,32,34–36 with preferential expression of TLR4 on the maternal facing plasma membrane of trophoblast reported.36 Similarly, choriocarcinoma cell lines are positive for cell surface TLR2 and TLR4 and for intracellular TLR9.33 Functional activity of TLR2, TLR3 and/or TLR4 has been reported for first- and third-trimester trophoblast/placenta,32,34,37–39 and choriocarcinoma cell lines are responsive to stimulation through TLR2, TLR3, TLR4 and TLR9 ligands.33

Of particular interest, the inflammatory cells infiltrating the preterm placenta of women with chorioamnionitis express TLR4, and TLR4 expression on the villous Hofbauer cells is increased in comparison with preterm placenta without chorioamnionitis as well as term placentas with or without chorioamnionitis.35 This suggests a potential role for villous Hofbauer cells in the activation of the innate immune system in response to infectious pathogens that can initiate PTL.

The expression of other PRRs, such as the cytoplasmic nucleotide-binding oligomerisation domain (NOD, namely NOD1 and NOD2), has been demonstrated (mRNA and protein) in first-trimester placenta and primary trophoblast where they were functional.40 This would provide an additional level of antimicrobial protection in the absence of a sufficient response mediated through TLRs, but confirmation of expression in second- and third-trimester trophoblast is required.

Amnion

Amniotic epithelial cells also clearly possess the mechanisms necessary to specifically recognise and respond to bacteria. To date, only the expression of TLR2 and TLR4 by amniotic epithelial cells has been described. Upregulation of both receptors has been described for amniotic membranes from (i) women who delivered after spontaneous labour at term versus those who delivered at term without being in labour41 and (ii) women with chorioamnionitis versus those without.42 Interestingly, in cases without chorioamnionitis, TLR2 expression was confined to the basal surface of amniotic epithelial cells, and this polarisation was lost in the presence of inflammation.42 This expression pattern is analogous to TLR5 expression in non-inflamed versus inflamed gastrointestinal epithelium, supporting the hypothesis that a pathogen must breach certain barriers before a response can be mounted.43

Decidua

The decidua contains many cell types that are able to produce a variety of inflammatory mediators and with the potential to mount an immune response against a pathogen. Term decidual cells express TLR1, TLR2, TLR4 and TLR6, and these receptors are functional.44 TLR2 and TLR4 protein also have been detected in infiltrating cells, most likely macrophages and neutrophils, during inflammation of term deciduas.42 Thus, expression of TLRs by cells within the decidua suggests a role for these cells in the response to an invasive infection or the initiation of labour.

Myometrium

At the time of writing, there were no studies on TLR expression and/or activity in the human myometrium published.

Mechanisms of action of TLR

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cytokines and labour
  5. Toll-like receptors
  6. TLRs at the maternal-fetal interface
  7. Mechanisms of action of TLR
  8. TLR signalling pathways
  9. TLR and term and PTL
  10. Clinical perspective
  11. Summary
  12. References

The known mammalian TLR family of PRRs have a unique structure comprising three parts: an extracellular portion consisting of leucine-rich repeats, typically between 18 and 31; a very short transmembrane domain and a cytoplasmic domain known as the Toll/IL-1 receptor (TIR) domain as it shares a conserved domain of approximately 200 amino acids with the IL-1 receptor. Ligand specificity is provided by the extracellular leucine-rich repeats and makes each receptor unique. The extracellular domain functions as a sentinel for ‘molecular patterns’ on both exogenous/microbial (bacterial/viral RNA/DNA, LPS and lipopeptides) as well as endogenous/host-derived (human heat shock proteins and host RNA) products (Table 1). With the exception of TLR10, microbial ligands for each of the TLR family members have been described. The existence of endogenous ligands (i.e. host-derived) indicates TLR signalling during normal physiological phenomena is probable.

Table 1.  Exogenous (microbial) and endogenous (host-derived) ligands for TLR1–11*
TLRMicrobial ligandsNatural ligands
  • *

    Note that TLR11 has not been demonstrated as functional in humans.24

TLR1Triacetylated lipoproteins (with TLR2) 
TLR2Gram-positive peptidoglycan, lipopeptides, lipoteichoic acids (Mycoplasma), zymosan (fungal hyphae and conidia) 
TLR3Double-stranded viral RNA (polyinosine-polycytidylic acid)Host RNA45
TLR4Gram-negative LPSNeutrophil elastase,46 heat shock proteins,47 fibronectin48
TLR5Bacterial flagellin 
TLR6Zymosan (fungal hyphae and conidia), diacetylated lipoproteins (with TLR2) 
TLR7Single-stranded RNA, small synthetic compounds, R848, loxoribine, bropirimine 
TLR8Single stranded RNA, small synthetic compounds, R848, loxoribine, bropirimine 
TLR9Unmethylated CpG DNAChromatin-IgG complexes49
TLR10Unknown 
TLR11Profilin (Toxoplasma gondii) 

Each TLR forms either a homodimer (two identical receptor chains) or heterodimer (two different receptor chains) for the recognition of a specific or set of specific molecular determinants present on microorganisms. TLR1, TLR2, TLR4, TLR5 and TLR6 tend to specialise in the recognition of bacterial products that are present on the outer surfaces of microorganisms, whereas TLR3, TLR7, TLR8 and TLR9 specialise in recognising nucleic acids, especially those of viral origin. Discrimination of microbial nucleic acids from those of the host is mediated not so much by the molecular nature of the ligands as by their accessibility to the relevant TLRs.50 These TLRs (3, 7, 8 and 9) are typically localised in intracellular compartments, especially late endosomes–lysosomes, where host nucleic acids are not normally found.51

Activation of a TLR results in an inflammatory immune response characterised by the production of cytokines, interferons (IFNs), chemokines and other antimicrobial factors.52 Furthermore, through the regulation of co-stimulatory molecule expression (and cytokine production) by dendritic cells, TLRs facilitate the development of the adaptive immune response.27 Each TLR has both common effects shared by other receptors but also specific functions. Thus, while individual TLRs respond to a limited number of ligands, collectively the family of TLRs can respond to a wide range of products associated with bacteria, viruses, fungi and protozoa.

TLR signalling pathways

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cytokines and labour
  5. Toll-like receptors
  6. TLRs at the maternal-fetal interface
  7. Mechanisms of action of TLR
  8. TLR signalling pathways
  9. TLR and term and PTL
  10. Clinical perspective
  11. Summary
  12. References

As already mentioned, the intracellular domain of TLRs shares its structure with that of IL-1 receptor family members hence its name, TIR domain. This TIR domain is pivotal to the initiation of intracellular signalling events. Intracellular signalling through TLRs can be divided broadly into two types—that dependent on the adapter protein myeloid differentiation factor 88 (MyD88) and MyD88-independent signalling. Other than TLR3, all TLRs use MyD88-dependent signalling pathways, whereas TLR3 uses only MyD88-independent signalling and TLR4 alone uses both MyD88-dependent and MyD88-independent signalling. Currently, there are four known adapter proteins involved in the initiation of mammalian TLR intracellular signalling cascades through their ability to interact with the TIR domain of TLRs. A fifth adapter protein has been described, sterile α and HEAT-Armadillo motifs, but a role for this in TLR signalling in humans has not been revealed.53

MyD88 was the first adapter protein to be identified, and it binds to all TLRs except TLR3.54 A sequential series of phosphorylation/dephosphorylation events of a cascade of signalling molecules and transcription factors leads ultimately to activation of a key transcription factor, NF-κB. Once activated NF-κB can enter the nucleus and bind to the promoter region within DNA encoding various inflammatory (and other) genes and thereby promote the transcription of DNA into RNA leading ultimately to the production and secretion of protein. Many of the proteins produced through this pathway are key inflammatory mediators, including TNF-α and IL-8. Note that an additional transcription factor, activating protein-1, has also been implicated in the expression of inflammatory genes after stimulation through TLRs. A second adapter protein called TIR domain-containing adapter protein (TIRAP) has been shown to have an essential role in MyD88-dependent signalling through TLR2 and TLR4 but not through TLR7 and TLR9.55 A third adapter protein has a key role in MyD88-independent signalling through TLR3 and TLR4 and is called TIR domain-containing adapter protein inducing IFN-β (TRIF). TRIF interacts directly with TLR3, whereas the interaction of TRIF with TLR4 requires an intermediate (and fourth family member) adapter protein known as TRIF-related adapter molecule (TRAM).56,57 These two TRIF-dependent MyD88-independent pathways (TLR3 and TLR4) can activate either NF-κB for inflammatory gene expression or IFN regulatory factors (IRFs) for production of type I IFNs (IFN-α and IFN-β). Even though signalling by TLR7, TLR8 and TLR9 is MyD88-dependent, activation through these pathways also leads to production of type I IFNs (as well as inflammatory gene expression through NF-κB), but the events linking TLR7, TLR8, TLR9 and MyD88 to IRFs and type I IFN production have not been identified. However, the IRF family member(s) used in MyD88-dependent pathways (as used by TLR7, TLR8 and TLR9) differ to those associated with MyD88-independent induction of type I IFNs (as used by TLR3 and TLR4).58 For the sake of simplicity, the extensive array of molecules involved in linking the adapter molecules and the crucial transcription factors have not been discussed (Figure 2).

image

Figure 2. MyD88-dependent and MyD88-independent signalling of TLRs 1–10. The four adapter proteins known to be functional in humans are shown as are the downstream effects of each of these pathways on the induction of inflammatory gene expression and/or production of type I IFNs. Note that the ligand(s) and intracellular signalling pathways for TLR10 have not been elaborated but that TLR10 is phylogenetically most closely related to TLR1, TLR2 and TLR6.59 TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 are expressed on the cell surface membrane, whereas TLR3, TLR7, TLR8 and TLR9 are expressed on the membranes of intracellular endosomes. IFN, Interferons; TIRAP, TIR domain-containing adapter protein; TRAM, TRIF-related adapter molecule.

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Although the TLR family, together with other PRRs, have presumably evolved to provide an immediate protective response to danger signals such as those from pathogenic bacteria, viruses and host cells damaged by infectious agents, unconstrained or inappropriate activation of these same pathways can be detrimental to the host. In extreme cases, this can lead to sepsis and autoimmune disease. Therefore, negative regulation is required to control the activity of these pathways. An ever increasing number of inhibitors of these signalling pathways are being described, although so far these are generally limited to the TLR2 and TLR4 signalling pathways, which are the most extensively studied TLR signalling pathways. One of the key molecules recruited to MyD88 once it is associated with a TLR is one of the IL-1 receptor-associated kinase (IRAK) family members. Of the four IRAKs described to date, IRAK1 and IRAK4 are activating, whereas IRAK2 and IRAKM negatively regulate TLR signalling as they lack the intrinsic kinase activity required to catalyse the next step in the intracellular signalling cascade. IRAKM has been particularly implicated in the phenomenon of tolerance to TLR ligands.60 Single immunoglobulin IL-1 receptor-related (SIGIRR) protein inhibits LPS-mediated activity by attenuating the recruitment of the initial signalling components to TLR461 and Tollip (toll-interacting protein) is a negative regulator of both TLR2 and TLR4.62 There are also inhibitors that act extracellularly to inhibit the binding of ligand to receptor.63

TLR and term and PTL

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cytokines and labour
  5. Toll-like receptors
  6. TLRs at the maternal-fetal interface
  7. Mechanisms of action of TLR
  8. TLR signalling pathways
  9. TLR and term and PTL
  10. Clinical perspective
  11. Summary
  12. References

Knowing that TLRs are expressed and functional in various gestation-associated tissues, a logical hypothesis is that there is a role for these receptors in the onset and/or maintenance of labour in response to microbial stimuli at preterm and endogenous ligands at term. Although some physiological roles of proinflammatory cytokines at the maternal-fetal interface have been described with regard to growth of the placenta and deciduas,64 excessive or aberrant production of proinflammatory cytokines such as IL-1β, TNF-α and IFN-γ at the maternal-fetal interface is generally considered harmful to pregnancy. NF-κB, a key transcription factor in TLR-mediated signalling pathway, has been implicated by a number of groups in the regulation of proinflammatory cytokine and prostaglandin production by gestation-associated tissues. For example, NF-κB activity is low in amnion epithelial cells obtained before labour and increased at the time of labour65 and is essential for basal and IL-1β stimulated IL-8 production by primary amnion cells and a cervical epithelial cell line.66 Thus, NF-κB, possibly subsequent to activation of TLRs (Figure 2), might have a critical role in signalling pathway(s) that increase inflammatory cytokine production and antimicrobial peptides in gestation-associated tissues.

Elevated concentrations of inflammatory mediators, such as cytokines and prostaglandins, in the amniotic fluid and extraembryonic tissues occur in pregnancies with demonstrable microbial invasion of the maternal-fetal interface, and inflammation is now recognised as a mechanism for preterm parturition.67 Numerous studies have found a link between the treatment of various gestation-associated tissues with microbial stimuli and cytokine output34,68 responses that are now recognised as likely to be mediated through TLRs. TLR agonists such as LPS can trigger the production of key molecular events ultimately leading to the production of relevant cytokines. Bacterial infection can occur in the choriodecidual space, fetal membranes, or within the amniotic fluid, placenta, umbilical cord or fetus.67 Ascending infection from the urinary or genital tract is considered to be the most common route of infection, however, haematogenous spread of organisms from the other sites, such as opportunistic pathogens like Fusobacterium nucleatum from the oral cavity, is of increasing interest.69 Thus, TLRs expressed by various cell populations at the maternal-fetal interface will recognise and respond to conserved bacterial/viral motifs and increase the production of various inflammatory cytokines that have autocrine and paracrine effects that can lead to the initiation of labour (Figure 1). To date, functional TLR4 has been implicated in PTL triggered by administration of heat-killed Escherichia coli to mice.70 Evidence of a role for TLRs in infection-associated PTL also comes from the genetic studies. A polymorphism (Asp299Gly) known to be associated with impaired TLR4 function and an increased likelihood of Gram-negative sepsis71 was carried more often by preterm infants than by term infants or by mothers delivering at preterm than at term.72

In addition to the direct proinflammatory effects initiated by exposure to infection, disturbances in trophoblast survival through elevated apoptosis (programmed cell death) in response to stimulation through TLRs might also have a role in preterm birth73,74 as well as other suboptimal pregnancy outcomes, such as intrauterine growth restriction or pre-eclampsia.75,76

Clinical perspective

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cytokines and labour
  5. Toll-like receptors
  6. TLRs at the maternal-fetal interface
  7. Mechanisms of action of TLR
  8. TLR signalling pathways
  9. TLR and term and PTL
  10. Clinical perspective
  11. Summary
  12. References

The study of TLR-mediated inflammation at the maternal-fetal interface has only just begun. A better understanding of these receptors and the signal transduction cascades they initiate might explain why some pregnancies are complicated by PTL and preterm prelabour rupture of membranes (PPROM), whereas others are only affected by PPROM. Moreover, investigations into the endogenous activators of TLRs might explain how PTL and PPROM can occur in the absence of infection. Histological and in vitro studies suggest that the solution to prevention of PTL might be the rapid suppression of inflammatory reactions triggered by microbial products before the irreversible initiation and propagation of positive feed-forward cascades that precipitate PTL. Either TLRs or their signalling molecules might be excellent targets for therapeutic strategies because they are upstream mediators of the proinflammatory cascade that ultimately results in PTL.

The search for agonists and antagonists of TLRs and there associated adapter molecules and signalling intermediates for the treatment of an array of diseases including autoimmune diseases, asthma and septic shock are underway.77,78 However, as more than one TLR can be involved in the response to an infectious agent targeting common aspects of these pathways, such as the adapter proteins or intracellular signalling molecules, might be the best strategy. The transcription factor NF-κB serves as a focal point for inflammatory mediators such as TNF-α, LPS and various TLRs, and accumulating evidence implicates a role for NF-κB in the physiology and pathophysiology of labour.79 Thus, NF-κB is an ideal candidate target for the prevention and treatment of PTL, and in vitro studies addressing the ability of blocking NF-κB activity to ablate relevant labour-promoting pathways are underway.80

Summary

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cytokines and labour
  5. Toll-like receptors
  6. TLRs at the maternal-fetal interface
  7. Mechanisms of action of TLR
  8. TLR signalling pathways
  9. TLR and term and PTL
  10. Clinical perspective
  11. Summary
  12. References

Spontaneous term labour and infection-associated PTL feasibly can be mediated by the same TLR signalling pathways. The common outcome would be elevated proinflammatory cytokine production and effects of these mediators on gestation-associated tissues for the initiation and maintenance of labour. A better understanding of TLRs and their signalling cascades is of relevance to labour both at term and preterm (and possibly other pregnancy complications). Further studies in this field are continuing and will lead to the discovery of much needed ‘novel targets’ for either prevention of labour when preterm or induction of labour at term.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cytokines and labour
  5. Toll-like receptors
  6. TLRs at the maternal-fetal interface
  7. Mechanisms of action of TLR
  8. TLR signalling pathways
  9. TLR and term and PTL
  10. Clinical perspective
  11. Summary
  12. References