REVIEW ARTICLE: Interleukin‐10: A Multi‐Faceted Agent of Pregnancy

Abstract

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 due to 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 mediator of cross-talk between the placenta and the decidua. Importantly, we utilize investigations into adverse pregnancy conditions to further elucidate the multifarious role of IL-10 at the maternal-fetal interface.

Vitamin D and the Regulation of Placental Inflammation

“…Moreover, recent reports demonstrating direct effects of 1,25(OH) 2 D 3 on the generation of regulatory T cells (29) suggest that impaired synthesis of this hormone in the placenta may have wider consequences for tolerogenic immune responses during pregnancy, even in the absence of an immune challenge. IL-10 is produced by regulatory T cells and other cells (including villous cytotrophoblasts) within the placenta, where it appears to function as a key facilitator of successful pregnancy (30). Analysis of placental tissue has shown reduced levels of IL-10 in pre-eclampsia pregnancies (31); thus, it was interesting to note the decreased expression of this cytokine in Cyp27b1 2/2 placentas.…”

The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF–trophoblast–IL-10 axis via Stat1 inhibition and Stat3 activation

“…19,20 Moreover, IL-10 is noted for its abilities to inhibit Mw proliferation by activating Stat3 33 and Trophoblast-mediated deactivation of macrophages A Dallagi et al to suppress IFN-c-mediated functions of Mws by blocking Stat1 activation. 34 In the pregnant human uterus, IL-10 is produced in large amounts by both the syncytiotrophoblast and the decidual Mws, 9,10,28,29 while LIF is highly expressed by decidual Mws and uNK cells. 35 On the other hand, the IL-10 receptor is constitutively expressed on placental trophoblasts 28,29 and decidual Mws are known to be highly responsive to IL-10.…”

“…34 In the pregnant human uterus, IL-10 is produced in large amounts by both the syncytiotrophoblast and the decidual Mws, 9,10,28,29 while LIF is highly expressed by decidual Mws and uNK cells. 35 On the other hand, the IL-10 receptor is constitutively expressed on placental trophoblasts 28,29 and decidual Mws are known to be highly responsive to IL-10. 9,10 In contrast, the expression level of LIF receptors is significantly higher in both villous and extravillous trophoblasts than in the decidua, 35 suggesting that all cells of the trophoblast lineage are major targets for the action of LIF in the placenta.…”

“…27 Another important gestational factor is IL-10, which is a type-2 cytokine that is expected to play a key role in pregnancy immunotolerance through the establishment of a Th2 immune response at the maternal2fetal interface. 28,29 IL-10 inhibits the production of several pro-inflammatory cytokines, including TNF-a in Mws and IFN-c in NK cells, thereby preventing the development of type-1 immune reactions that are deleterious for both the establishment and maintenance of pregnancy. [30][31][32] Thus, using the IL-10 KO mice model to study LPS-induced preterm parturition, Murphy et al 19,20 demonstrated that in the absence of IL-10, IFN-c-producing uNK cells may exert cytotoxic functions through TNF-a production and invasiveness into the placental zone, leading to fetal demise or intrauterine fetal growth restriction.…”

Associations of maternal immune response with MeHg exposure at 28 weeks’ gestation in the Seychelles Child Development Study

“…61 Similarly, low concentrations of IL-4 and IL-10 have been observed in the decidua from women suffering from unexplained recurrent abortions and where spontaneous abortion has occurred during the first trimester of pregnancy. 62 Data on the association of Hg, in particular MeHg, with IL-10 are limited and more research is required to ascertain any immunomodulatory effects of MeHg on IL-10 and IL-4 at critical periods of development during pregnancy.…”