Role of astrocytes in reproduction and neuroprotection.
Hypothalamic astrocytes secrete TGF-beta and 3 alpha,5 alpha-tetrahydro progesterone (3 alpha,5 alpha-THP) in culture. When the astrocyte-conditioned medium (ACM) was incubated with the hypothalamic cell line GT1-7, it resulted in the secretion of GnRH. Immunoneutralization with TGF-beta antibody or ultra-filteration with a 10 kDa cut off filter resulted in attenuation of the GnRH releasing ability of ACM, indicating that TGF-beta was a major factor involved with GnRH release. Treatment with estrogens increases TGF-beta secretion. These observations indicate a significant role of astrocytes in GnRH secretion. Serum-deprivation results in the death of GT1-7 neurons in culture and addition of ACM or TGF-beta to the culture, attenuates cell death. The mechanism of protection from cell death appears to involve phosphorylation of MKK4, JNK, c-Jun(Ser63), and enhancement of AP-1 binding. Co-administration of JNK inhibitors, but not MEK inhibitors attenuated ACM or TGF-beta-induced c-Jun(Ser63) phosphorylation and their neuroprotective effects. These studies suggest that astrocytes can protect neurons, at least in part, by the release of TGF-beta and activation of a c-Jun/AP-1 protective pathway.
Mahesh
Virendra B
VB
Institute of Molecular Medicine and Genetics, Program in Neurobiology, and Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA. vmahesh@mail.mcg.edu
Dhandapani
Krishnan M
KM
Brann
Darrell W
DW
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology*; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012098:Reproduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology; D053773:Transforming Growth Factor beta1
D004967:Estrogens; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D007987:Gonadotropin-Releasing Hormone