title: Dose-dependent biphasic leptin-induced proliferation is caused by non-specific IL-6/NF-κB pathway activation in human myometrial cells.
abstract: OBJECTIVE
  Leptin, an adipokine synthesized by the placenta during pregnancy, has been proposed for the management of preterm labour (PTL), as it is able to prevent in vitro uterine contractility and remodelling associated with labour onset. Another common feature of labour onset is the phenotypic switch of myometrial smooth muscle cells from a proliferative to a hypertrophic state. As proliferative effects have been demonstrated for leptin in other tissues, we aimed to investigate its ability to induce myometrial proliferation and thus to maintain uterine quiescence.
  
  
  METHODS
  We stimulated human primary myometrial smooth muscle cells with leptin in the presence or absence of receptor antagonists or signalling pathway inhibitors.
  
  
  RESULTS
  Leptin induced myometrial cell proliferation in a biphasic manner. At 6.25 ng · mL(-1), leptin-induced proliferation was mediated by the leptin receptor and required the early activation of ERK1/2. At a concentration above 25 ng · mL(-1), leptin induced direct non-specific stimulation of the IL-6 receptor, leading to NF-κB activation, and exerted anti-proliferative effects. However, at 50 ng · mL(-1), leptin re-induces proliferation via IL-6 receptor stimulation that requires STAT3 and delayed ERK1/2 activation.
  
  
  CONCLUSIONS
  These data bring new insights into leptin signalling-induced myometrial proliferation and its interrelationship with the IL-6/IL-6 receptor axis. In the light of our previous work, the present study emphasizes the potential value of leptin in the pharmacological management of PTL and it also strengthens the hypothesis that leptin might be a contributory factor in the parturition-related disorders observed in obese women.
authors: INSERM, U866, Equipe labellisée ligue contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors: Marina
authors: M
authors: Barrichon
authors: INSERM, U866, Equipe labellisée ligue contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors: Tarik
authors: T
authors: Hadi
authors: INSERM, U866, Equipe labellisée ligue contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.|Centre Hospitalier Universitaire de Dijon, Dijon, France.
authors: Maeva
authors: M
authors: Wendremaire
authors: INSERM, U866, Equipe labellisée ligue contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors: Clémentine
authors: C
authors: Ptasinski
authors: INSERM, U866, Equipe labellisée ligue contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors: Renaud
authors: R
authors: Seigneuric
authors: INSERM, U866, Equipe labellisée ligue contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.
authors: Guillaume
authors: G
authors: Marcion
authors: Clinique Sainte-Marthe, Dijon, France.
authors: Marc
authors: M
authors: Delignette
authors: Clinique Sainte-Marthe, Dijon, France.
authors: Jacques
authors: J
authors: Marchet
authors: INSERM, U866, Equipe labellisée ligue contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.|Centre Hospitalier Universitaire de Dijon, Dijon, France.
authors: Monique
authors: M
authors: Dumas
authors: Centre Hospitalier Universitaire de Dijon, Dijon, France.|Service de Gynécologie & Obstétrique, Dijon, France.
authors: Paul
authors: P
authors: Sagot
authors: INSERM, U866, Equipe labellisée ligue contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.|Centre Hospitalier Universitaire de Dijon, Dijon, France.|INSERM CIC-P 803, Dijon, France.
authors: Marc
authors: M
authors: Bardou
authors: INSERM, U866, Equipe labellisée ligue contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.|Anti-cancer Center George-François Leclerc, Dijon, France.
authors: Carmen
authors: C
authors: Garrido
authors: INSERM, U866, Equipe labellisée ligue contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne, Dijon, France.|Centre Hospitalier Universitaire de Dijon, Dijon, France.
authors: Frédéric
authors: F
authors: Lirussi
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D020738:Leptin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009215:Myometrium / Q000166:cytology / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D011247:Pregnancy; D054411:Receptors, Leptin / Q000187:drug effects* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015850:Interleukin-6; D020738:Leptin; D016328:NF-kappa B; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor
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