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.
Highlights
To identify the role of Notch signaling during preterm labor induced by toll-like receptor (TLR) ligands, the expression of Notch ligand (DLL-1), its receptors (Notch[1, 2, 3] and 4) and the transcription factor Hes[1] were assessed at the feto-maternal interface during preterm labor after intrauterine administration of PGN+ poly(I:C) in mice[19,23]
Double immunofluorescence staining of F4/80 and DLL-1 ligand shows that PGN+ poly(I:C) induces DLL-1 ligand in decidual macrophages (Fig. 1A)
We further explored Notch signaling in decidual macrophages obtained from mice on day 14.5 of normal pregnancy and cultured ex vivo
Summary
This combination of PGN+ poly(I:C) induces the preterm labor via simultaneous activation of apoptosis and inflammatory processes[24] Such combined stimulation of TLR2 and TLR3 receptors results in simultaneous activation of both known TLR downstream signaling pathways, known as the MyD88 (myeloid differentiation primary response gene 88)-dependent and the MyD88-independent pathways. Suppression of Notch signaling ex vivo using gamma secretase inhibitor (GSI) significantly diminished PGN+ poly(I:C)-induced inflammation and reduced the secretion of VEGF. These distinct opposing effects of PGN+ poly(I:C) on inflammation-associated Notch ligand (DLL-1) and angiogenesis-associated Notch ligands (DLL4, Jagged 1 and 2) signify that Notch signaling pathways are modulated bidirectionally during PGN+ poly(I:C)-induced preterm labor. Instead of its bidirectional effect, GSI treatment was able to increase in-utero survival of the fetuses and prevents PGN+ poly(I:C)-induced preterm delivery by 55.5%
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