title: Notch Signaling in Inflammation-Induced Preterm Labor.
abstract: Notch signaling plays an important role in regulation of innate immune responses and trophoblast function during pregnancy. To identify the role of Notch signaling in preterm labor, Notch receptors (Notch1-4), its ligands (DLL (Delta-like protein)-1/3/4), Jagged 1/2) and Notch-induced transcription factor Hes1 were assessed during preterm labor. Preterm labor was initiated on gestation day 14.5 by intrauterine (IU) injection of peptidoglycan (PGN) and polyinosinic:cytidylic acid (poly(I:C). Notch1, Notch2, Notch4, DLL-1 and nuclear localization of Hes1 were significantly elevated in uterus and placenta during PGN+poly(I:C)-induced preterm labor. Ex vivo, Gamma secretase inhibitor (GSI) (inhibitor of Notch receptor processing) significantly diminished the PGN+poly(I:C)-induced secretion of M1- and M2-associated cytokines in decidual macrophages, and of proinflammatory cytokines (IFN-γ, TNF-α and IL-6) and chemokines (MIP-1β) in decidual and placental cells. Conversely, angiogenesis factors including Notch ligands Jagged 1/2 and DLL-4 and VEGF were significantly reduced in uterus and placenta during PGN+poly(I:C)-induced preterm labor. In vivo GSI treatment prevents PGN+poly(I:C)-induced preterm delivery by 55.5% and increased the number of live fetuses in-utero significantly compared to respective controls 48 hrs after injections. In summary, Notch signaling is activated during PGN+poly(I:C)-induced preterm labor, resulting in upregulation of pro-inflammatory responses, and its inhibition improves in-utero survival of live fetuses.
authors.affiliation: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jaiswal
authors.affiliation: Department of Obstetrics and Gynecology, NorthShore University Health System, Evanston, IL.
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, IL, USA.
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, IL, USA.
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, IL, USA.
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, IL, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Gilman-Sachs
authors.affiliation: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Beaman
authors.affiliation: Department of Obstetrics and Gynecology, NorthShore University Health System, Evanston, IL.|Department of Obstetrics and Gynecology, Pritzker School of Medicine, University of Chicago, Chicago, IL.
authors.forename: Emmet
authors.initials: E
authors.lastname: Hirsch
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D007752:Obstetric Labor, Premature; D010457:Peptidoglycan / Q000494:pharmacology; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011070:Poly I-C; D011119:Polynucleotides / Q000494:pharmacology; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000072056:Transcription Factor HES-1; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018925:Chemokines; D016207:Cytokines; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010457:Peptidoglycan; D011070:Poly I-C; D011119:Polynucleotides; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C512941:DLK1 protein, human; C078493:HES1 protein, human