Key message
Blocking interleukin (IL)11 during mid to late gestation pregnancy in mice did not affect pregnancy viability,
Placental development is highly regulated spatially and temporally by numerous factors, such as cytokines, which can determine the success or failure of pregnancy (Salamonsen et al., 2009). Impaired placentation can be characterized by inadequate extravillous trophoblast (EVT) invasion (Brosens et al, 1972, Pijnenborg, 1994) and remodelling of the decidual arteries, which is completed early in the second trimester in humans (Naicker et al, 2003, Staff et al, 2013). The abnormal placenta, which bathes in maternal blood, releases factors into the blood causing maternal systemic inflammation and widespread endothelial dysfunction, which lead to the symptoms of pre-eclampsia (Redman and Sargent, 2005).
Pre-eclampsia is a pregnancy-induced disorder characterized by hypertension and proteinuria, and is a major cause of maternal and perinatal morbidity and mortality, affecting approximately 8% of pregnancies (Sibai et al., 2005). Alarmingly, those women that survive are at increased risk of developing severe complications, including chronic kidney and cardiovascular disease and have an increased risk of dying within 12 months of giving birth (Eiland et al., 2012). Advances in the prevention and treatment of pre-eclampsia have been hampered by poor understanding of the aetiology (Kaufmann et al., 2003). Nevertheless, there is substantial evidence showing abnormal placentation is crucial to the underlying cause (reviewed by Roberts and Escudero, 2012). Clinically diagnosed most often in the late second or third trimester, the only current treatment for pre-eclampsia is placental delivery.
Interleukin (IL)11 is a member of the IL6 family of cytokines that signals via the IL11 receptor (R)α chain and gp130, to form a heterodimeric complex (Heinrich et al., 1998). It is well established that IL11 activates the janus kinase (JAK) signal transducers and activators of transcription (STAT)3 pathway in the human endometrium (Dimitriadis et al., 2006), primary human EVT and placental villous (Paiva et al, 2007, Paiva et al, 2009, Winship et al, 2015c), as well as the mouse placenta and decidua (Winship et al., 2015c). In women, IL11 and IL11Rα localize to the placenta; produced by syncytiotrophoblast and cytotrophoblast cells in the chorionic villi, as well as endovascular EVT during the first trimester (Paiva et al., 2007). In mice, both IL11 and IL11Rα localize to placental labyrinth and endovascular trophoblast and endothelial cells in mouse implantation sites throughout gestation (Winship et al., 2015c), reflecting the expression pattern in women and implying a role in placentation in vivo.
IL11 has well-established functional roles in the cycling endometrium and in the early initiation of pregnancy during endometrial stromal cell decidualization (Bilinski et al, 1998, Dimitriadis et al, 2000, Dimitriadis et al, 2002, Robb et al, 1998, White et al, 2007). Female mice with a null mutation in IL11Rα are infertile due to defective decidualization that leads to resorption of the embryo by E10 of gestation (Bilinski et al, 1998, Robb et al, 1998). Our research group utilized an IL11 mutein antagonist ligated to polyethylene glycol (PEGIL11A) to block IL11 signalling in the mouse uterine lumen following intraperitoneal administration during early post-implantation, demonstrating that IL11 is only required for decidual formation during early gestation in mice (Menkhorst et al., 2009).
IL11 levels are elevated in serum, placenta (Winship et al., 2015c) and decidua (Basar et al., 2010) of women with pre-eclampsia. In vitro, IL11 impedes primary human first trimester EVT cell invasion (Paiva et al., 2007) and placental villous outgrowth (Sonderegger et al., 2011) required for normal placentation. In mice, elevated levels of IL11 during placentation impair trophoblast invasion and spiral artery remodelling and recapitulate the hallmark features of pre-eclampsia and intrauterine growth restriction (IUGR) (Winship et al., 2015c). In the same study, withdrawal of IL11 after the onset of hypertension and proteinuria rescued pre-eclampsia features in mice, suggesting that IL11 signalling inhibition could provide a novel treatment option. In women and mice, decidual IL11Rα protein levels are significantly reduced during the second trimester or mid-gestation, respectively (Winship et al., 2015c), highlighting the potential feasibility of targeting IL11 during mid to late gestation to ameliorate pre-eclampsia in women, without affecting the decidua, or pregnancy viability.
We postulated that blocking IL11 action temporally during mid to late gestation would not alter pregnancy viability. We aimed to determine the effect of antagonizing IL11Rα on the placenta, decidua, fetus and maternal peripheral organs affected during pre-eclampsia. We also examined the effect of blocking IL11Rα on subsequent female fertility, 1 month after the cessation of treatment.
Female (virgin 8-week-old) and male C57BL/6J mice (Monash Animal Services, Clayton, Australia) were housed under conventional conditions, with food and water available ad libitum and a 12 h light–dark cycle. All procedures were approved by the Monash Medical Centre Animal Ethics Committee on 19 July 2012 (reference number MMCB/2012/17). This study followed the NHMRC Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. C57BL/6 mice were mated. The time of
Exogenous IL11 administration from E10–13 was previously reported to alter mouse placental labyrinth development (Winship et al., 2015c), therefore we determined the effect of PEGIL11A on mouse placental development from E10–13. Implantation sites (E13) were collected from mice treated with PEGIL11A or PEG control. There were no differences in the number of viable (PEGIL11A 8.00 ± 0.40; PEG 8.75 ± 0.48) or resorbed (PEGIL11A 1.50 ± 0.29; PEG 1.25 ± 0.25) implantation sites between groups (
IL11 is up-regulated in serum, decidua and placenta of women with pre-eclampsia (Winship et al., 2015c) and may be useful as a target to treat pre-eclampsia, usually diagnosed at >20 weeks of gestation. IL11 also has critical roles in decidualization and trophoblast invasion, two processes required for the establishment of pregnancy in the first trimester. The decidualization defect and resorption of embryos at E10 in IL11Rα knockout mice have been a limiting factor for the investigation of the
The authors acknowledge CSL Limited for providing the PEGIL11A and PEG control reagents. This work was supported by NHMRC Australia Project Grant (1078674) and the Victorian Government's Operational Infrastructure Support Program. AW was supported by a Cancer Council Victoria Postdoctoral Fellowship. ED was supported by a NHMRC Australia Senior Research Fellowship (550905).
Eva Dimitriadis is Senior Research Fellow (NHMRC), Head of the Embryo Implantation Laboratory, Hudson Institute and adjunct Professor at Monash University. She discovered a novel epigenetic communication method between human embryos and endometrium, recognized by awards from the Society for Gynaecological Investigation and the Society for Reproductive Biology. Key message Blocking interleukin (IL)11 during mid to late gestation pregnancy in mice did not affect pregnancy viability,
Animal experiments suggest that the “critical window” for developmental toxicity of dexamethasone might coincide with the specific period for embryonic organ development (Lajic et al., 2011; Miller and Witchel, 2013; Ortiz et al., 2003; LaBorde et al., 1992). GD12-14 and GD15-17 were reported to be in mid- and late-gestation period in mice, respectively (Winship et al., 2018; Zhou et al., 2015). Our results demonstrated that PDE at therapeutic dose during GD12–14 or GD15–17 can induce embryonic developmental retardation in mice, which is consistent with the results found in other groups (Neuhaus et al., 2015; Zhou et al., 2015).
Eva Dimitriadis is Senior Research Fellow (NHMRC), Head of the Embryo Implantation Laboratory, Hudson Institute and adjunct Professor at Monash University. She discovered a novel epigenetic communication method between human embryos and endometrium, recognized by awards from the Society for Gynaecological Investigation and the Society for Reproductive Biology. Key message Blocking interleukin (IL)11 during mid to late gestation pregnancy in mice did not affect pregnancy viability, including normal decidual, placental, fetal or offspring morphology. These findings highlight the exciting potential of IL11 signalling inhibition as a safe therapeutic to treat pregnancy complications, or as a novel fertility-preserving anti-cancer agent.