title: Role of Notch signaling during lipopolysaccharide-induced preterm labor.
abstract: Notch signaling pathways exert effects throughout pregnancy and are activated in response to TLR ligands. To investigate the role of Notch signaling in preterm labor, Notch receptors (Notch1-4), its ligand Delta-like protein-1, transcriptional repressor hairy and enhancer of split-1, and Notch deregulator Numb were assessed. Preterm labor was initiated on gestation d 14.5 by 1 of 2 methods: 1) inflammation-induced preterm labor: intrauterine injection of LPS (a TLR4 agonist) and 2) hormonally induced preterm labor: subcutaneous injection of mifepristone. Delta-like protein-1, Notch1, and hairy and enhancer of split-1 were elevated significantly, and Numb was decreased in the uterus and placenta of inflammation-induced preterm labor mice but remained unchanged in hormonally induced preterm labor compared with their respective controls. F4/80(+) macrophage polarization was skewed in the uterus of inflammation-induced preterm labor toward M1-positive (CD11c(+)) and double-positive [CD11c(+) (M1) and CD206(+) (M2)] cells. This process is dependent on activation of Notch signaling, as shown by suppression of M1 and M2 macrophage-associated cytokines in decidual macrophages in response to γ-secretase inhibitor (an inhibitor of Notch receptor processing) treatment ex vivo. γ-Secretase inhibitor treatment also diminished the LPS-induced secretion of proinflammatory cytokines and chemokines in decidual and placental cells cultured ex vivo. Furthermore, treatment with recombinant Delta-like protein-1 ligand enhanced the LPS-induced proinflammatory response. Notch ligands (Jagged 1 and 2 and Delta-like protein-4) and vascular endothelial growth factor and its receptor involved in angiogenesis were reduced significantly in the uterus and placenta during inflammation-induced preterm labor. These results suggest that up-regulation of Notch-related inflammation and down-regulation of angiogenesis factors may be associated with inflammation-induced preterm labor but not with hormonally induced preterm labor.
authors.affiliation: Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, Illinois, USA; varkhaagrawal@gmail.com.
authors.forename: Varkha
authors.initials: V
authors.lastname: Agrawal
authors.affiliation: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA; and.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jaiswal
authors.affiliation: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA; and.
authors.forename: Sahithi
authors.initials: S
authors.lastname: Pamarthy
authors.affiliation: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA; and.
authors.forename: Gajendra K
authors.initials: GK
authors.lastname: Katara
authors.affiliation: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA; and.
authors.forename: Arpita
authors.initials: A
authors.lastname: Kulshrestha
authors.affiliation: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA; and.
authors.forename: Alice
authors.initials: A
authors.lastname: Gilman-Sachs
authors.affiliation: Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, Illinois, USA; Department of Obstetrics and Gynecology, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Emmet
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA; and.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Beaman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003656:Decidua / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D007752:Obstetric Labor, Premature / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D008070:Lipopolysaccharides; D051880:Receptors, Notch
keywords: DLL-1 ligand; angiogenesis; inflammation; macrophage polarization; mifepristone