title: Targeting Inhibitor of κB Kinase β Prevents Inflammation-Induced Preterm Delivery by Inhibiting IL-6 Production from Amniotic Cells.
abstract: Preterm delivery (PTD) remains a serious challenge in perinatology. Intrauterine infection and/or inflammation, followed by increased inflammatory cytokines, represented by IL-6, are involved in this pathology. Our aim was to identify IL-6-producing cells in the placenta and to analyze the potential of targeting IκB kinase β (IKKβ) signaling to suppress IL-6 production for the treatment of PTD. Immunohistochemical analyses using placentas complicated with severe chorioamnionitis revealed that IL-6 is mainly expressed in human amniotic mesenchymal stromal cells (hAMSCs). Primary hAMSCs were collected, and strong IL-6 expression was confirmed. In hAMSCs, the treatment of tumor necrosis factor-α or IL-1β drastically induced IL-6 production, followed by the phosphorylation of IKKs. A novel IKKβ inhibitor, IMD-0560, almost completely inhibited IL-6 production from hAMSCs. Using an experimental lipopolysaccharide-induced PTD mouse model, the therapeutic potential of IMD-0560 was examined. IMD-0560 was delivered vaginally 4 hours before lipopolysaccharide administration. Mice in the IMD-0560 (30 mg/kg, twice a day) group had a significantly lower rate of PTD [10 of 22 (45%)] without any apparent adverse events on the mice and their pups. In uteri collected from mice, IMD-0560 inhibited not only IL-6 production but also production of related cytokines, such as keratinocyte-derived protein chemokine/CXCL1, macrophage inflammatory protein-2/CXCL2, and monocyte chemoattractant protein-1/chemokine ligand 2. Targeting IKKβ signaling shows promising effects through the suppression of these cytokines and can be explored as a future option for the prevention of PTD.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Aska
authors.initials: A
authors.lastname: Toda
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address: daasawada@gyne.med.osaka-u.ac.jp.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sawada
authors.affiliation: IMMD Inc., Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujikawa
authors.affiliation: Laboratory of Infection and Prevention Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Wakabayashi
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Sawada
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Nakatsuka
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Kinose
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kae
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Mabuchi
authors.affiliation: Department of Obstetrics and Gynecology, Toyonaka Municipal Hospital, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tokuhira
authors.affiliation: Department of Clinical Laboratory Medicine and Anatomic Pathology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: IMMD Inc., Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Itai
authors.affiliation: Department of Obstetrics and Gynecology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kurachi
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000650:Amnion / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D002821:Chorioamnionitis / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000150:complications*; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D047928:Premature Birth / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*
chemical_list: D001549:Benzamides; D015850:Interleukin-6; D008070:Lipopolysaccharides; C503742:N-(2,5-bis(trifluoromethyl)phenyl)-5-bromo-2-hydroxybenzamide; D051550:I-kappa B Kinase