Interleukin-11 alters placentation and causes preeclampsia features in mice

Abstract

Preeclampsia (PE) is a pregnancy-specific disorder characterized by hypertension and proteinuria after 20 wk gestation. Abnormal extravillous trophoblast (EVT) invasion and remodeling of uterine spiral arterioles is thought to contribute to PE development. Interleukin-11 (IL11) impedes human EVT invasion in vitro and is elevated in PE decidua in women. We demonstrate that IL11 administered to mice causes development of PE features. Immunohistochemistry shows IL11 compromises trophoblast invasion, spiral artery remodeling, and placentation, leading to increased systolic blood pressure (SBP), proteinuria, and intrauterine growth restriction, although nonpregnant mice were unaffected. Real-time PCR array analysis identified pregnancy-associated plasma protein A2 (PAPPA2), associated with PE in women, as an IL11 regulated target. IL11 increased PAPPA2 serum and placental tissue levels in mice. In vitro, IL11 compromised primary human EVT invasion, whereas siRNA knockdown of PAPPA2 alleviated the effect. Genes regulating uterine natural killer (uNK) recruitment and differentiation were down-regulated and uNK cells were reduced after IL11 treatment in mice. IL11 withdrawal in mice at onset of PE features reduced SBP and proteinuria to control levels and alleviated placental labyrinth defects. In women, placental IL11 immunostaining levels increased in PE pregnancies and in serum collected from women before development of early-onset PE, shown by ELISA. These results indicate that elevated IL11 levels result in physiological changes at the maternal-fetal interface, contribute to abnormal placentation, and lead to the development of PE. Targeting placental IL11 may provide a new treatment option for PE.placenta | trophoblast | cytokines | pregnancy P reeclampsia (PE) is a pregnancy-induced disorder characterized by hypertension and proteinuria, unique to humans, affecting ∼8% of pregnancies (1). The etiology is poorly understood (2); nevertheless, there is substantial evidence showing abnormal placentation is the key underlying cause. During pregnancy, highly invasive extravillous trophoblasts (EVT) acquire vascular-like properties to remodel uterine spiral arterioles. This creates low-resistance, large-diameter vessels that promote uteroplacental blood supply to sustain fetal growth (3, 4). It is widely accepted that inadequate trophoblast invasion and impaired uterine spiral artery remodeling is an initiating factor in the development of PE (5). This is thought to impair uteroplacental arterial flow and lead to placental oxidative stress (6). PE is associated with increased placental secretion of proinflammatory cytokines (7) and angiogenic regulators (8), thought to contribute to widespread maternal endothelial dysfunction. The clinical symptoms of PE are hypertension, proteinuria, and peripheral and/or cerebral edema. Symptoms can differentially manifest during the second (early-onset, EO), or third (late-onset, LO) trimester (9). In addition to the maternal symptoms, PE is also frequently associated with prematurit...

Maternal Vascular Physiology in Preeclampsia

“…IL-11, a member of the gp130 family, has been shown to inhibit extravillous trophoblastic invasion and spiral artery remodeling. 92,93 Circulating IL-11 is significantly increased, and placental IL-11 is upregulated in women with early-onset versus late-onset preeclampsia. 93 Pregnant mice treated with IL-11 exhibit preeclampsia-like features.…”

Porphyromonas gingivalis strain-dependent inhibition of uterine spiral artery remodeling in the pregnant rat†

“…A plethora of cytokines within the uterine microenvironment such as IL-1β, IL-6, IL-10, IL-11, IL-15, TNF-α, and the transforming growth factor beta (TGF-β) superfamily including the activins regulate EVT invasion and spiral artery remodeling during normal pregnancy [7][8][9][10][11]. Derangements in some of these factors have been shown to inhibit EVT invasion in vitro or disrupt implantation and placentation in vivo [11][12][13][14]. It is notable that periodontal bacteria, which have been detected in the placenta of women with preeclampsia [15][16][17], can elicit cytokine and chemokine responses from decidual cells [18] that could reduce EVT invasion and spiral artery remodeling [11].…”

Two N-Linked Glycans Differentially Control Maturation, Trafficking and Proteolysis, but not Activity of the IL-11 Receptor

“…pancreatic cancer [8], breast cancer with bone metastasis [9], acute pancreatitis [10] and arthritis [11]. IL-11 causes preterm birth [12] and features of preeclampsia in mice [13]. Furthermore, IL-11 has been described as the key cytokine of the IL-6 family in gastrointestinal tumorigenesis, thereby offering a potential therapeutic target [14].…”