title: Human Chorionic Gonadotropin Has Anti-Inflammatory Effects at the Maternal-Fetal Interface and Prevents Endotoxin-Induced Preterm Birth, but Causes Dystocia and Fetal Compromise in Mice.
abstract: Human chorionic gonadotropin (hCG) is implicated in the maintenance of uterine quiescence by down-regulating myometrial gap junctions during pregnancy, and it was considered as a strategy to prevent preterm birth after the occurrence of preterm labor. However, the effect of hCG on innate and adaptive immune cells implicated in parturition is poorly understood. Herein, we investigated the immune effects of hCG at the maternal-fetal interface during late gestation, and whether this hormone can safely prevent endotoxin-induced preterm birth. Using immunophenotyping, we demonstrated that hCG has immune effects at the maternal-fetal interface (decidual tissues) by: 1) increasing the proportion of regulatory T cells; 2) reducing the proportion of macrophages and neutrophils; 3) inducing an M1 → M2 macrophage polarization; and 4) increasing the proportion of T helper 17 cells. Next, ELISAs were used to determine whether the local immune changes were associated with systemic concentrations of progesterone, estradiol, and/or cytokines (IFNgamma, IL1beta, IL2, IL4, IL5, IL6, IL10, IL12p70, KC/GRO, and TNFalpha). Plasma concentrations of IL1beta, but not progesterone, estradiol, or any other cytokine, were increased following hCG administration. Pretreatment with hCG prevented endotoxin-induced preterm birth by 44%, proving the effectiveness of this hormone as an anti-inflammatory agent. However, hCG administration alone caused dystocia and fetal compromise, as proven by Doppler ultrasound. These results provide insight into the mechanisms whereby hCG induces an anti-inflammatory microenvironment at the maternal-fetal interface during late gestation, and demonstrate its effectiveness in preventing preterm labor/birth. However, the deleterious effects of this hormone on mothers and fetuses warrant caution.
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Amy-Eunice
authors.initials: AE
authors.lastname: Furcron
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan Center for Molecular Obstetrics and Genetics, Wayne State University, Detroit, Michigan.
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Tara N
authors.initials: TN
authors.lastname: Mial
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan.
authors.forename: Amapola
authors.initials: A
authors.lastname: Balancio
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Panaitescu
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Hassan
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Aashna
authors.initials: A
authors.lastname: Sahi
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan.
authors.forename: Claire
authors.initials: C
authors.lastname: Nord
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan nardhy.gomez-lopez@wayne.edu ngomezlo@med.wayne.edu.
authors.forename: Nardhy
authors.initials: N
authors.lastname: Gomez-Lopez
mesh_terms: D000818:Animals; D006063:Chorionic Gonadotropin / Q000009:adverse effects / Q000627:therapeutic use*; D003656:Decidua / Q000187:drug effects / Q000276:immunology*; D004420:Dystocia / Q000139:chemically induced*; D004731:Endotoxins; D004958:Estradiol / Q000097:blood; D005260:Female; D005333:Fetus / Q000187:drug effects*; D053583:Interleukin-1beta / Q000097:blood; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D047928:Premature Birth / Q000139:chemically induced / Q000517:prevention & control*; D011374:Progesterone / Q000097:blood; D016216:Ultrasonography, Prenatal
chemical_list: D006063:Chorionic Gonadotropin; D004731:Endotoxins; D053583:Interleukin-1beta; D011374:Progesterone; D004958:Estradiol
keywords: M1 macrophages; M2 macrophages; Th17 cells; decidua; estradiol; hCG; interleukin-1β; mouse; neutrophils; parturition; pregnancy; preterm labor; progesterone; regulatory T cells