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Effects of Cytokines on Gonadotropin-Releasing Hormone (GnRH) Gene Expression in Primary Hypothalamic Neurons and in GnRH Neurons Immortalized Conditionally

Service of Endocrinology (P.I., R.S., J.-P.R., M.G., F.P.P., R.C.G.), Diabetology and Metabolism, Department of Medicine, University Hospital, CH-1011 Lausanne, Switzerland; Service of Endocrinology (F.P.P.), Diabetology and Metabolism, University Hospital, 1211 Geneva, Switzerland

Address all correspondence and requests for reprints to: François Pralong, M.D., Service of Endocrinology, Department of Medicine, BH 19-709, CH-1011 Lausanne, Switzerland. E-mail: Francois.Pralong{at}chuv.ch.

Various cytokines produced during the immune reaction can modulate the neuroendocrine reproductive axis, probably by inducing changes in the activity of hypothalamic GnRH neurons. However, the precise cellular and molecular effects of cytokines on these neurons have not been reported yet. To gain a better insight into these regulations, we first examined the pattern of expression of cytokine receptors in a novel neuronal cell line expressing GnRH (Gnv-4 cells). Among others, gp130 is expressed in Gnv-4 cells, together with the ligand receptor subunits specific for IL-6 as well as oncostatin M (OSM). Consistent with the latter observation, we show that OSM stimulates the expression of the immediate early genes c-fos and early growth response-1 in Gnv-4 cells, an effect dependent upon the activation of the MAPK Erk1/2 intracellular signaling pathway. Functional studies performed in parallel in Gnv-4 cells and in primary hypothalamic neuronal cell cultures show that OSM, although devoid of any effect of its own on GnRH gene expression, can inhibit dose-dependently the stimulation of GnRH expression by N-methyl-D-aspartic acid. In conclusion, these data demonstrate that a GnRH-expressing neuronal cell line can be modulated in vitro by cytokines implicated in the regulation of the reproductive axis. Moreover, they provide the first evidence of an involvement of OSM in these regulations.

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