Leukemia inhibitory factor (LIF), a pleiotropic cytokine of the interleukine-6 superfamily, is involved in several functions including the control of reproduction at the embrionic-endometrial interface and the regulation of energy homeostasis. LIF activates a cell-surface receptor complex (LIF-Rs) composed of one ligand-specific low affinity LIF receptor β (LIFR-β) subunit and the gp-130 subunit. Since little is known about the involvement of LIF in the modulation of the neuroendocrine circuitry governing the reproductive function and, specifically, of the migration of gonadotrophin releasing-hormone (GnRH) neurons from the olfactory placode to the hypothalamus, we tested whether LIF could exert a chemoattractant or chemotropic action on GN11 immortalized cells, an in vitro model of immature and migratory GnRH neurons. GN11 cells were found to express LIFR-β and gp130 subunits at both gene and protein level. Exposure to LIF (100 ng/ml) activated Janus kinases (Jak)-signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK)-extracellular regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3-K)-Akt pathways. The selective inhibition of Jaks, MEK, and PI3-K indicated that in GN11 cells the three signalling pathways were activated independently and that Jak2 is not the main Janus kinase involved in LIF signalling. LIF stimulated chemotaxis at a concentration-dependent manner, reaching a plateau at 100 ng/ml both after 3 and 20 h of incubation. A 3-h treatment with 100 ng/ml LIF also induced chemokinesis. All the three signalling pathways activated by LIF in GN11 cells were independently involved in LIF-induced cell migration. In conclusions, the present results indicate that LIF promotes the chemomigration of immature GnRH neurons, and suggest that LIF might modulate the development of the reproductive axis by directly influencing the migration of GnRH neurons to the hypothalamus.
01 - 05 Apr 2006
European Society of Endocrinology