Tumor necrosis factor α reduces gonadotropin-releasing hormone release through increase of forkhead box protein O1 activity.

It has been found that hypothalamus helps to control aging, and hypothalamus-driven programmatic aging is associated with nuclear factor-kappa B (NF-kappa B)-mediated decrease of gonadotropin-releasing hormone (GnRH). However, the molecular mechanism(s) underlying aging-associated hypothalamic GnRH decline are largely unknown. Forkhead box O (FOXO), a family of transcription factors, has been demonstrated to be associated with aging. GnRH neuronal cell line GT1-7 was used in this study to determine whether FOXO1 was involved in tumor necrosis factor alpha (TNF-alpha)-induced decrease of GnRH. Our data showed that FOXO1 activity was increased by TNF-alpha through inhibition of its phosphorylation. Increased FOXO1 activity inhibited gnrh1 gene and activated NF-kappa B, thereby impairing the secretion of GnRH from GT1-7 cells. The increase of FOXO1 activity contributes to TNF-alpha-induced decrease of GnRH release, which may underscore the significance of this event to the development of aging and therapeutic interventions against age-dependent pathologies.