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Keywords:

  • Angiogenesis;
  • cross talk;
  • inflammation;
  • interleukin-10;
  • pregnancy;
  • toll-like receptor

Abstract

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References

Citation Thaxton JE, Sharma S. Interleukin-10: a multi-faceted agent of pregnancy. Am J Reprod Immunol 2010

It is widely accepted that pregnancy constitutes a unique developmental event. Unprecedented intrauterine actions of angiogenesis, immunity, and neuroendocrine regulation are juxtaposed to mechanisms of senescence that enable fetal growth and protection. The suppressive and regulatory factors that facilitate healthy pregnancy are under investigation. In non-pregnant systems of infection and inflammation, the cytokine interleukin-10 (IL-10) has been widely investigated because of its potential as a key immunosuppressant in response to a multitude of inflammatory events. In the context of pregnancy, IL-10 levels increase markedly in women during early pregnancy and remain elevated well into the third trimester immediately prior to onset of labor. The role of IL-10 during pregnancy as a suppressor of active maternal immunity to allow acceptance of the fetal allograft has been a point of study. Moreover, secretion of IL-10 by a diverse set of maternal and fetal cells has proven to aid in the orchestration of normal processes of pregnancy. Interestingly, some of the more profound findings regarding the actions of IL-10 during pregnancy have manifested from research that focuses on aberrant pregnancy outcomes as a result of inflammation, hormonal imbalances, or gene–environment interactions. This review focuses on the role of IL-10 as a facilitator of successful pregnancy both as an immune suppressive agent and a mediator of cross talk between the placenta and the decidua. Importantly, we discuss investigations on adverse pregnancy conditions to further elucidate the multifarious role of IL-10 at the maternal–fetal interface.


Discovery of IL-10

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References

Interleukin-10 was first reported by Mosmann et al. under the name of cytokine synthesis inhibitory factor (CSIF) as a protein with the ability to inhibit the activity of inflammatory T-helper 1 (Th1)-type cells.1 Investigation led to the deduction that CSIF was the major factor that defined a difference between Th1-type and Th2-type T-cells as CSIF skewed T-cell activity toward inhibition. Although originally defined as a product of Th2 cells, this cytokine has now been shown to be produced by a wide set of cell types, including both immune and non-immune cells.2 Reports also demonstrated that one mode of IL-10 regulation is through a feedback loop that curtails excessive inflammatory events. For example, when monocytes are activated with lipopolysaccharide (LPS), a dual cytokine response is induced where pro-inflammatory cytokine production is countered by production of IL-10.3

IL-10 began to flood the literature as a prominent cytokine that works in an autocrine and paracrine manner in response to the inflammatory limb of the immune system to sequester over-activation of pro-inflammatory signals. The capacity of IL-10 as a suppressive agent was bolstered by evidence that Epstein Barr Virus (EBV) contained a genomic insert with homology to the human IL-10 gene. It is hypothesized that EBV acquired the hIL-10 gene through evolution as a means to increase anti-viral responses during host infection.4 Importantly, research also showed IL-10 could act as a growth factor for lymphoid and myeloid cells under certain conditions, indicating that IL-10 was not solely an immunosuppressant.5

Protein, gene, receptor, signaling

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References

X-ray crystallography confirmed that IL-10 is an acid-sensitive homodimeric protein. Genetic data demonstrate that IL-10 is encoded on chromosome 1 of both mouse and humans, and mIL-10 and hIL-10 are fairly conserved in their amino acid sequences sharing ∼73% homology. hIL-10 and mIL-10 span 4.7 kb and 5.1 kb chromosome regions, respectively, yet both active forms are encoded by a series of five exons.2 Recent reports provide evidence for genetically mediated regulation of IL-10 production. Although several polymorphic changes have been identified in the IL-10 gene promoter, three sites at the −1082 (G/A), −819 (C/T), and −592 (C/A) positions have been best characterized for their regulatory influence. Later in this review, we report that multiple cohort studies show single nucleotide polymorphisms (SNPs) in the promoter region of the IL-10 gene may correlate with increased susceptibility to particular adverse conditions of pregnancy.6–10

The IL-10 receptor is composed of two subunits, IL-10R1 and IL-10R2, known members of the interferon receptor family (IFNR). Expression of IL-10R is reported on hemopoietic as well as non-hemopoietic cells.11 IL-10R1 is constitutively expressed on placental cytotrophoblasts.12 IL-10R1 is mainly necessary for the binding of the IL-10 protein while IL-10R2 is specific to initiate a signaling cascade. IL-10R2−/− mice behave like IL-10−/− mice, indicating that the second subunit of the receptor is essential for IL-10 signaling. The most well-described signaling pathway specific for IL-10 binding is that of the Jak/STAT pathway. Briefly, Tyk2 and Jak1 are recruited to the IL-10R1/2 complex. Upon Jak1/Tyk2-mediated phosphorylation of the cytoplasmic tail of the receptors, STAT3 is recruited and its phosphorylation allows homodimerization and entry into the nucleus for transcription of IL-10-regulated genes. Importantly, the STAT3 complex also induces transcription of the protein SOCS3 that triggers a negative feedback loop of IL-10 regulation by blocking subsequent phosphorylation of Jak1.11

IL-10: a pregnancy compatible cytokine

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References

Several clinical observations regarding pregnancy implicate a role of an anti-inflammatory regulator such as IL-10.13 A significant number of women with rheumatoid arthritis (RA), an inflammation-driven condition, consistently reported diminished symptoms during pregnancy. In contrast, women with systemic lupus erythematosus (SLE), an antibody-driven autoimmune disease, presented with increased symptoms during pregnancy. Taken together, these reports supported the postulate that an anti-inflammatory milieu, perhaps dominated by IL-10, was amplified during pregnancy most likely as a mechanism of tolerance toward the fetal allograft.

Initial studies of the role of IL-10 during pregnancy were carried out in mice. Murine decidual tissues harvested across the spectrum of gestation showed that IL-10 was produced in supernatants and peaked at gestational day (gd)12.14 Administration of recombinant IL-10 in abortion prone CBA×DBA/2 mice significantly abrogated the incidence of spontaneous fetal loss.15 In placental tissue obtained from normal pregnant women, immunohistochemical analysis coupled with ELISA showed that IL-10 was produced in a gestational age–dependent manner. Levels of IL-10 from first and second trimester placental tissues were significantly higher than levels found in third trimester tissues, suggesting that IL-10 is intrinsically downregulated at term to prepare for the onset of labor programmed by production of an inflammatory milieu.16

Further studies elucidated the crucial role of IL-10 at the maternal–fetal interface as placental and decidual tissue from first trimester missed abortions showed decreased IL-10 production when compared to control tissues obtained from first trimester elective terminations.17 Similarly, a comparison of placental tissue from elective cesarean (pre-labor) and placental tissue obtained post-labor showed higher IL-10 production in pre-labor tissues. Importantly, high IL-10 production in pre-labor tissues correlated to low prostaglandin-2 (PGE-2) levels, whereas the opposite held true for post-labor tissues.18 These data established IL-10 as a key contributor to the balance of pro-inflammatory versus anti-inflammatory signals that orchestrate proper pregnancy outcomes. Figure 1 presents a contemporary view of temporal potential of IL-10 at different stages of pregnancy.

image

Figure 1.  Inflammatory versus anti-inflammatory limbs of gestation. Starting from implantation through term gestation, the interplay of inflammatory and anti-inflammatory signaling events is central to normal pregnancy outcomes. Here, we represent the suppressive nature of IL-10 over the course of human gestation in contrast to the temporal presence of inflammatory signals.

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Ten years later, the role of IL-10 in pregnancy as an immunosuppressive agent is solidified, and recent studies have focused on its mechanistic properties. Investigation of pregnant IL-10−/− mice, when housed in a pathogen-free facility, showed that IL-10−/− litter size and term of gestation were similar to those observed in congenic wild-type (WT) mice.19 Interestingly, IL-10−/− mice showed increased placental size and larger areas of maternal blood sinuses when compared to WT controls.20 These data elucidated a role of IL-10 as a mediator of placental growth and remodeling. It is noteworthy that extravillous trophoblasts from first trimester exhibit poor IL-10 production while expressing high levels of message for matrix metalloproteinase-9 (MMP9), implying that invading trophoblasts may temporally downregulate IL-10 expression to maintain their invasive, not necessarily endovascular, potential.21

Cell types contributing to IL-10 production at the maternal–fetal interface

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References

Trophoblasts

The maternal–fetal interface is composed of trophoblast cells of fetal origin intermingled with specialized maternal lymphocytes, stromal cells, and endothelial cells that comprise the decidua. Here, we highlight studies that have defined the production of IL-10 by trophoblast cells and subsets of maternal uterine lymphocytes and summarize recent literature that delves into the intricate network of cellular cross talk that mediates this control.

A conundrum in the field of reproductive immunology is the presence of uterine natural killer cells (uNK) throughout the decidua. NK cells operate through the missing self-hypothesis where lack of major histocompatability complex (MHC) antigen presentation on a target cell leads to activation of the NK cells and resultant cytotoxicity.22 In an organ that was once considered immune-privileged, it is difficult to rationalize the presence of NK cells. However, it has been postulated that the expression of non-classical MHC type I molecule HLA-G on trophoblasts, particularly those with extravillous differentiation, plays a regulatory role in controlling NK cell cytotoxic activation.23 Interestingly, IL-10 has been shown to induce HLA-G on trophoblasts.24 HLA-G is present in different isoforms and has become a focus of an intense debate for the exact role that it plays.

While the mechanisms of HLA-G-based antigen presentation remain to be fully elucidated, the role of IL-10 as both a paracrine and autocrine regulator of trophoblast activity is apparent. Although villous cytotrophoblasts produce IL-10, it is not clear how trophoblast differentiation and invasion are controlled at this level. IL-10 decreases MMP9 transcription in villous cytotrophoblasts.21,25 This could be one mechanism by which cytotrophoblasts are selected for further differentiation and invasion. Compared to villous cytotrophoblasts, extravillous trophoblasts are intrinsically poor in IL-10 production, thus allowing MMP expression and invasion competency. This may require paracrine activity within the placental meshwork.12,26–28 It is noteworthy that simultaneous activity of progesterone and IL-10 on trophoblasts may work to sequester pro-inflammatory responses and to enhance regulated cross talk between the placenta and the decidua.29

uNK Cells and Monocytes

Uterine NK cells and monocytes are two major immune populations present in the decidua during pregnancy. These cells have the ability to produce and to be regulated by IL-10.30,31 Importantly, the characteristic immune functions of these cells, normally identified as cytotoxic killers, are altered in the context of pregnancy where their ability to aid in angiogenesis and placental regulation is paramount. The role of uNK cells in placental growth is discussed later in this review in the context of functional studies undertaken in our laboratory.

Several human studies lend evidence to the regulation of uNK cells or monocytes by IL-10. First trimester tissue from human surgical abortions was obtained, and lymphocytes were isolated. IL-10 production was assessed in comparison to peripheral blood mononuclear cells (PBMCs). Baseline IL-10 production from uterine monocytes and uNK cells was significantly elevated above PBMC production. Furthermore stimulation with LPS of these cells enhanced production of IL-10, indicating that a pro-inflammatory stimulus can elicit a suppressive cytokine response in the context of the uterine milieu.18,32 Finally, primary human uterine monocytes were isolated from decidual tissues obtained post-labor, and pre-labor (cesarean), and production of IL-10 was measured via ELISPOT. IL-10 from pre-labor tissue was markedly increased above post-labor levels, and this correlated to an increase in COX-2 mRNA signal in post, but not pre, labor tissues.33 These findings highlight the necessity of inflammatory signals to induce labor that couple to mechanisms aimed at silencing the action of IL-10.

Important insights into the immunological capabilities of uNK cells and decidual monocytes at the maternal–fetal interface have come from a mouse models of pregnancy established in our laboratory and others. We have studied IL-10−/− mice and their WT counterparts for pregnancy outcomes in response to exposure to inflammatory agents on gd6 or gd14, to mimic early pregnancy loss or preterm birth, respectively. Briefly, toll-like receptors (TLRs) are a group of innate immune receptors that recognize different pathogenic motifs. Injection of various TLR agonists at different gestational ages mimics maternal infection and allows for assessment of adverse pregnancy outcomes because of dysregulation of decidual immunity in the presence or absence of IL-10.

Studies with LPS, a TLR4 agonist, in IL-10−/− and WT mice induced fetal resorption (FR) or preterm birth on gd12 or gd17, respectively. Importantly, we found that IL-10−/− mice were highly susceptible to low doses of LPS, but WT mice required at least a 50-fold higher dose to induce adverse pregnancy outcomes. Dysregulation of innate immunity was similar in IL-10−/− and WT mice in that uNK cells became cytotoxic, produced TNF-α, and infiltrated the placental zone.19,34 Similar results were observed in response to TLR9 agonist CpG. Negative pregnancy outcomes were induced in IL-10−/− mice at very low doses of CpG whereas WT mice responded negatively only when doses were increased 20-fold. Importantly, investigation of the cellular immune dysregulation showed that macrophages, not uNK cells, were activated to produce TNF-α and infiltrate the placental zone.35 Taken together, these results demonstrate that in response to certain pathogens, IL-10 is a protective agent. Furthermore, the absence of IL-10 allows investigation of the pathogenesis of bacterial and viral motifs at sub-clinical levels. On the other hand, as a simple rule of nature, IL-10 cannot be presented as a global suppressive agent against all infectious agents. Our recent results are intriguing in that IL-10 does not protect pregnancy against mimics which represent double stranded RNA viruses (unpublished observations).

T Regulatory Cells

T regulatory (Tregs) cells in the decidua have recently come under the microscope of pregnancy research. Their characteristic ability to produce suppressive cytokines in response to foreign antigen makes Tregs promising therapeutic targets for intervention toward adverse pregnancy outcomes. Tregs are characterized as CD4+/CD25+/Foxp3+, and their ability to produce IL-10 is well documented.36 The presence of Tregs was assessed in the murine decidua. Unpublished data from our laboratory and others show that murine Tregs appear in the estrous cycle and increase early in pregnancy, peaking on gd10–12 and declining thereafter.37,38 Spontaneous fetal resorption in abortion prone CBA×DBA/2 mice can be abrogated by adoptive transfer of Tregs harvested from same gestational age WT mice. Importantly, neutralization of IL-10 in the aforementioned experimental setting abolishes the ability of WT Tregs to rescue CBA×DBA/2 fetal resorption.39 Finally, recent observations in humans have shown that decidual Tregs can inhibit immune stimulation of conventional T cells through cell-cell contact or IL-10 production.40

Recent findings suggest that uterine Tregs may be of peripheral blood origin and their development toward the uterine phenotype may be under hormonal control.41 Migration studies with human decidual Tregs show that Tregs migrate to areas of hCG production. Women with ectopic pregnancies or spontaneous abortion show decreased IL-10 production coupled to low levels of Treg migration to trophoblast/hCG+ dense regions.42 Interestingly, murine CD4+/CD25 cells treated with E2 were converted to Foxp3+ T cells that produced IL-10, lending further evidence that Tregs may be under hormonal control.43 However, one study posits that decidual Treg development may be driven in part by the presence of paternal antigen as pseudopregnant females (mated with vasectomized males) showed increased levels of decidual Tregs.44 Unpublished data from our laboratory show that Treg numbers do not differ between WT and IL-10 null pregnancies over the spectrum of gestation. However, we have begun to address differences in functionality of Tregs from IL-10−/− versus WT mice. As Tregs from IL-10−/− mice are deficient in this cytokine, it is tempting to speculate that these Tregs may elicit a distinct regulatory role, particularly in response to inflammatory triggers. These studies may lend promising insights to Tregs as therapeutic targets because of their ability to influence pregnancy outcome through IL-10-dependent or independent mechanisms.

Cellular cross talk and IL-10 at the maternal-fetal interface

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References

While specific decidual cell subsets still remain to be characterized, the role of IL-10 is manifesting from breakthrough work regarding cross talk between different decidual immune cells. Recent research shows that gd12 murine trophoblasts co-cultured with dendritic cells (DCs)-induced uNK cells to expand and produce IL-10, demonstrating that uNK cells are a rich source of IL-10 which could be required for maintaining their non-cytotoxic phenotype.45,46. These data reveal that production of IL-10, and other pregnancy based cytokines, is context dependent and regulated by an intricate network of cellular cross talk based on the decidual milieu. This assertion is further supported by a recent report that explored the role of Galectin-1, an immunoregulatory glycan binding protein, in the context of pregnancy. Gal1−/− mice displayed increased rates of fetal loss when compared to WT counterparts. Injection of recombinant Gal-1 into Gal-1−/− mice rescued pregnancy. This was directly associated with an increased number of decidual tolerogenic DCs which in turn induced expansion of IL-10-producing Tregs. Importantly, IL-10 neutralization or Treg depletion upon Gal-1 reconstitution abrogated the rescue of pregnancy.47 Such a scenario could also be envisioned for human pregnancy (Fig. 2).These data show the existence of an intricate network of trophoblast-DC-IL-10-Treg-based fetal-tolerance that remains to be further elucidated.

image

Figure 2.  Cellular cross talk at the maternal–fetal interface and IL-10. Based on recent data, we have created a hypothetical model of cross talk between dendritic cells (DC), trophoblasts, uNK cells, the non-classical MHC I molecule HLA-G and T regulatory cells. Cellular interactions at the maternal–fetal interface are largely unknown, but studies sighted in this review begin to delineate the course of cell-cell regulation over the course of gestation. The main objective of this cellular cross talk is IL-10 production by uNK cells and T regulatory cells.

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IL-10-based gene-environment challenges and angiogenesis

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References

Successful pregnancy outcome is associated with immune tolerance and de novo angiogenesis at the maternal–fetal interface. Is there a link between these two events and does IL-10 contribute to angiogenesis? Our recent work provides evidence for both these processes. We have demonstrated that the non-cytotoxic phenotype of human uNK cells is maintained through production of vascular endothelial growth factor c (VEGF C) by these cells and VEGF C-mediated MHC class I expression on endothelial cells and trophoblasts.48,49 Interestingly, IL-10 was found to induce VEGF C production by first trimester trophoblast cells under certain conditions (unpublished observations). Along similar lines, our recent results invoke the role of the water channels aquaporins (AQPs), particularly, at the maternal–fetal interface. AQP1 is a potent effector of fluid volume regulation and is expressed in both human and mouse placenta. AQP1 plays an important role in angiogenesis, and our recent work demonstrates that expression of the AQP1 channel may be directly controlled by the presence of IL-10. We show that IL-10 induces the expression of aquaporin 1 (AQP1) in human trophoblasts as well as in murine placental tissues. Treatment with polychlorinated biphenyls (PCBs), ubiquitous environmental toxicants, abrogated this effect in IL-10−/− mice and induced preterm birth in response to the loss of AQP1. However, administration of recombinant IL-10 to PCB-treated IL-10 null mice restored expression of AQP1 and led to term pregnancy.50 Our unpublished data also suggest that IL-10 downregulates the Notch-dll4 axis, a nemesis of angiogenesis. As a corollary to our results, tumor cells are known to produce IL-10. It is tempting to speculate that IL-10 production by tumor cells programs their escape from immune surveillance and promotes angiogenesis.51 Taken together, these observations warrant a thorough analysis of IL-10 and aquaporins as angiogenic factors at the maternal–fetal interface (Fig. 3).

image

Figure 3.  A possible role of IL-10 in angiogenesis. This model highlights recent findings from our laboratory that showcase IL-10 as a growth factor because of its ability to induce trophoblast cells to enhance expression of aquaporin-1 and VEGFs.

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IL-10 deficiency and adverse pregnancy outcomes

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References

There have been several studies that couple IL-10 deficiency to adverse pregnancy outcomes such as recurrent spontaneous abortion (RSA), preterm birth, and pre-eclampsia. The mechanisms that may lead to poor IL-10 production at the maternal–fetal interface are not well understood. However, polymorphisms in the IL-10 gene promoter have been associated with dysregulated IL-10 production and several diseases. Recent studies have identified five SNPs at −3575, −2849, −1082, −819, and −592 positions in the human IL-10 gene promoter.52–55 Similarly, the molecular effects of these SNPs in the IL-10 gene promoter remain to be elucidated in the context of pregnancy complications. In the following sections, we provide a discussion on the association of IL-10 dysregulation and adverse pregnancy outcomes.

Pre-eclampsia

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References

Pre-eclampsia occurs in 5–10% of pregnancies worldwide and is a systemic disorder resulting from poor placentation. Although the pathogenesis of pre-eclampsia remains poorly understood, defective trophoblast invasion and spiral artery remodeling are thought to induce placental ischemia/hypoxia which eventually results in production of inflammatory molecules.56 Systemic presence of inflammatory molecules or dysregulation of essential proteins may then cause the maternal syndrome diagnosed by elevated blood pressure, proteinuria, kidney pathology, and edema.57 Does reduced production of IL-10 contribute to poor placentation and induction of inflammatory molecules? Curiously, evaluation of placental tissue and serum samples from pre-eclamptic women has suggested reduced IL-10 production.58,59 Serum samples from pre-eclamptic women disrupt endovascular interactions between trophoblasts and endothelial cells and lead to the full spectrum of pre-eclampsia-like features in IL-10−/− mice compared to WT mice (our unpublished observations). In this regard, research that links low levels of IL-10 coupled to decreased numbers of Tregs with this elusive disease of pregnancy may shed light on its causative agents.60

Based on our recent results, we surmise that IL-10 reconstitution prevents onset of pre-eclampsia-associated features in both in vivo and in vitro models of pre-eclampsia. There may also be a genetic link to pre-eclampsia, and analysis of SNPs in the IL-10 gene promoter is likely to provide insights into the nature of this disease. Interestingly, one genotype, −2849AA, is thought to be associated with a threefold reduced risk toward acquisition of pre-eclampsia.61

Recurrent spontaneous abortion and preterm birth

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References

Recurrent spontaneous abortion has been linked to an increase in CD56+ cells as well as an increase in TNF-α.62,63 However, the balance of this inflammatory cytokine may be skewed as a result of a lack of IL-10 production. PBMCs from women with RSA show increased cytotoxicity because of high levels of TNF-α, but levels of IL-10 production are significantly lower than control PBMCs.64,65 Similarly, PBMCs from women with RSA show lower production of IL-10 upon stimulation with trophoblastic antigen when compared to normal pregnancy controls.66 We have previously demonstrated that decidual and placental tissue from spontaneous abortions showed reduced presence of IL-10 with no effect on IFN-γ compared to tissue from elective terminations.17 Thus, poor IL-10 production coupled with increased production of inflammatory molecules may be a trigger for early pregnancy loss or preterm birth. Furthermore, placental explants obtained from women undergoing preterm labor showed poor IL-10 production coupled to elevated prostaglandin release when compared to normal pregnancy control samples.67

Based on these observations, we established mouse models for fetal resorption and preterm birth using IL-10−/− mice. As was aforementioned, our data are significant in that low doses of inflammatory triggers cause fetal loss or preterm birth depending on the gestational age–dependent exposure to the trigger.19,34,35 These pregnancy complications are strongly linked with immune programming in the form of cytotoxic activation of uterine NK cells, macrophages, or T cells and TNF-α production depending on the nature of the inflammatory trigger. These results provide impetus for further investigation into the nature of infection/inflammation and the ensuing immune responses in both mouse models and humans.

Summary

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References

It is well accepted now that IL-10 influences immune responses in a variety of ways. In the context of pregnancy, we propose that IL-10 exerts profound effects on linking immunity, angiogenesis, and maintenance of expression of molecules regulating fluid volume across the placenta. Our work in IL-10−/− mice for the first time provides important clues to the pathogenesis of fetal loss, preterm birth, and pre-eclampsia. These observations have given rise to the hope that IL-10-based therapy may some day become a reality for enigmatic pregnancy maladies.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References

We would like to thank Tania Nevers for insightful critique and reading of the manuscript. This work was supported in part by grants from NIH and NIEHS, P20RR018728 and Superfund Basic Research Program Award (P42ES013660). This work was also supported in part by the Rhode Island Research Alliance Collaborative Research Award 2009-28.

References

  1. Top of page
  2. Abstract
  3. Discovery of IL-10
  4. Protein, gene, receptor, signaling
  5. IL-10: a pregnancy compatible cytokine
  6. Cell types contributing to IL-10 production at the maternal–fetal interface
  7. Cellular cross talk and IL-10 at the maternal-fetal interface
  8. IL-10-based gene-environment challenges and angiogenesis
  9. IL-10 deficiency and adverse pregnancy outcomes
  10. Pre-eclampsia
  11. Recurrent spontaneous abortion and preterm birth
  12. Summary
  13. Acknowledgments
  14. References