Dose-dependent biphasic leptin-induced proliferation is caused by non-specificIL-6/NFkappaB pathway activation in human myometrial cells.
Fiche publication
Date publication
février 2015
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BARDOU Marc, Dr GARRIDO Carmen, Dr WENDREMAIRE Maeva
Tous les auteurs :
Barrichon M, Hadi T, Wendremaire M, Ptasinski C, Seigneuric R, Marcion G, Delignette M, Marchet J, Dumas M, Sagot P, Bardou M, Garrido C, Lirussi F
Lien Pubmed
Résumé
BACKGROUND AND PURPOSE: Leptin, an adipokine synthesized by the placenta during pregnancy, has been proposed for the management of preterm labor (PTL), since it is able to prevent in vitro uterine contractility and remodeling associated with labor onset. Another common feature of labor 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. EXPERIMENTAL APPROACH: We stimulated human primary myometrial smooth muscle cells with leptin in the presence or absence of receptors antagonists or signaling pathways inhibitors. KEY RESULTS: We found that leptin induces myometrial cell proliferation in a biphasic way. At 6.25ng/ml, leptin-induced proliferation is mediated by leptin receptor (OB-R) and requires an early Erk1/2 activation. Then, we demonstrated that at a concentration above 25ng/ml, leptin induces a direct non-specific IL-6R stimulation leading to NFkappaB activation and exerts anti-proliferative effects. However, at 50ng/ml, leptin re-induces proliferation via IL-6R stimulation that requires STAT3 and delayed Erk1/2 activation. CONCLUSIONS AND IMPLICATIONS: These data bring new insights into leptin signaling-induced myometrial proliferation and its interrelationship with the IL-6/IL-6R axis. In light of our previous work, the present study emphasizes the potential value of leptin in the pharmacological management of preterm labor and it also strengthens the hypothesis that leptin might be a contributory factor in parturition-related disorders observed in obese women.
Référence
Br J Pharmacol. 2015 Feb 5