Estrogen-astrocyte-luteinizing hormone-releasing hormone signaling:: A role for transforming growth factor-β1

The purpose of this study was to identify factors from astrocytes that can regulate LHRH neurosecretion. Exposure of LHRH-secreting (GT1-7) cells to conditioned media (CM) from C6 glial cells and hypothalamic astrocytes (HA) stimulated LHRH release. Assays of C6 and HA CM revealed that transforming growth factor-beta(1) (TGF-beta(1)) and 3 alpha-hydroxy-5 alpha-pregnane-20-one (3 alpha,5 alpha-THP), both known LHRH secretagogues, were present in CM and their levels increased in parallel to the LHRH-releasing activity of CM. In contrast, TGF-alpha was undetectable in C6 or HA CM. Ultrafiltration to remove peptides with molecular weights >10 kDa virtually abolished the LHRH-releasing ability of the HA CM. Furthermore, immunoneutralization with a panspecific THF-beta antibody dose-dependently attenuated the LHRH-releasing activity of the CM. Rat hypothalamus and GT1-7 cells were demonstrated to express TGF-beta receptors as well as furin, an enzyme that converts latent TGF-beta(1) to active TGF-B-1. Estrogen receptor-alpha and ER-beta mRNA and protein were also demonstrated in HAs by reverse transcription-polymerase chain reaction and double immunofluorescence, and treatment with 17 beta-estradiol (17 beta-E-2) increased both active and latent TGF-beta(1) levels in HA CM. The effect of 17 beta-E-2 was completely blocked by the ER antagonist ICI8280. As a whole, these studies provide evidence of a previously undescribed 17 beta-E-2-TGF-beta(1)-LHRH signaling pathway.