Dose-dependent biphasic leptin-induced proliferation is caused by non-specific IL-6/NF-B pathway activation in human myometrial cells (Publication with Expression of Concern. See DEC, 2024)

Background and PurposeLeptin, 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. Experimental ApproachWe stimulated human primary myometrial smooth muscle cells with leptin in the presence or absence of receptor antagonists or signalling pathway inhibitors. Key ResultsLeptin induced myometrial cell proliferation in a biphasic manner. At 6.25ngmL(-1), leptin-induced proliferation was mediated by the leptin receptor and required the early activation of ERK1/2. At a concentration above 25ngmL(-1), leptin induced direct non-specific stimulation of the IL-6 receptor, leading to NF-B activation, and exerted anti-proliferative effects. However, at 50ngmL(-1), leptin re-induces proliferation via IL-6 receptor stimulation that requires STAT3 and delayed ERK1/2 activation. Conclusions and ImplicationsThese 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.