title: 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.
authors.affiliation: Embryo Implantation Laboratory, Hudson Institute, Clayton, VIC 3168, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Department of Molecular and Translational Medicine, Monash University, Clayton, VIC 3800, Australia;
authors.forename: Amy L
authors.initials: AL
authors.lastname: Winship
authors.affiliation: Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan;
authors.forename: Kaori
authors.initials: K
authors.lastname: Koga
authors.affiliation: Embryo Implantation Laboratory, Hudson Institute, Clayton, VIC 3168, Australia; Department of Molecular and Translational Medicine, Monash University, Clayton, VIC 3800, Australia;
authors.forename: Ellen
authors.initials: E
authors.lastname: Menkhorst
authors.affiliation: Embryo Implantation Laboratory, Hudson Institute, Clayton, VIC 3168, Australia; Department of Molecular and Translational Medicine, Monash University, Clayton, VIC 3800, Australia;
authors.forename: Michelle
authors.initials: M
authors.lastname: Van Sinderen
authors.affiliation: Embryo Implantation Laboratory, Hudson Institute, Clayton, VIC 3168, Australia; Department of Molecular and Translational Medicine, Monash University, Clayton, VIC 3800, Australia;
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Rainczuk
authors.affiliation: Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan;
authors.forename: Miwako
authors.initials: M
authors.lastname: Nagai
authors.affiliation: Embryo Implantation Laboratory, Hudson Institute, Clayton, VIC 3168, Australia; Department of Molecular and Translational Medicine, Monash University, Clayton, VIC 3800, Australia;
authors.forename: Carly
authors.initials: C
authors.lastname: Cuman
authors.affiliation: Embryo Implantation Laboratory, Hudson Institute, Clayton, VIC 3168, Australia;
authors.forename: Joanne
authors.initials: J
authors.lastname: Yap
authors.affiliation: Cancer and Haemotology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia;
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.affiliation: School of Biomedical Sciences, University of Queensland, QLD 4072, Australia;
authors.forename: David
authors.initials: D
authors.lastname: Simmons
authors.affiliation: Department of Molecular and Translational Medicine, Monash University, Clayton, VIC 3800, Australia; Cardiovascular Endocrinology Lab, Hudson Institute, Clayton, VIC 3168, Australia.
authors.forename: Morag J
authors.initials: MJ
authors.lastname: Young
authors.affiliation: Embryo Implantation Laboratory, Hudson Institute, Clayton, VIC 3168, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Department of Molecular and Translational Medicine, Monash University, Clayton, VIC 3800, Australia; evdokia.dimitriadis@hudson.org.au.
authors.forename: Evdokia
authors.initials: E
authors.lastname: Dimitriadis
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003656:Decidua / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D010929:Placentation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D053702:Receptors, Interleukin-11 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017370:Interleukin-11; D053702:Receptors, Interleukin-11; D011994:Recombinant Proteins; C514948:PAPPA2 protein, mouse; D011266:Pregnancy-Associated Plasma Protein-A
keywords: cytokines; placenta; pregnancy; trophoblast