Regulation of cytokine-induced neuron death by ovarian hormones: involvement of antiapoptotic protein expression and c-JUN N-terminal kinase-mediated proapoptotic signaling.
Mechanisms underlying the divergent effects of ovarian hormones on neuron death induced by TNFalpha were investigated in differentiated PC12 cells (dPC12). dPC12 cells were exposed to 17beta-estradiol (E, 1.0 nm), progesterone (P, 100 nm), or a combination of both hormones for 0-72 h before treatment with TNFalpha (0-150 ng) to induce cell death. Cells undergoing apoptosis were identified by a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling assay and fluorescence-activated cell sorting after 18 h. Cell death induced by TNFalpha was decreased 89% after E treatment and increased 2-fold after P treatment compared with cells treated with TNFalpha alone. Treatment with E for 24 h before TNFalpha exposure was required for maximum neuroprotection, whereas P-enhanced death was maximal after a 30-min P treatment. TNFalpha induced a 3-fold increased activity of c-JUN-N-terminal kinase (JNK) 1 in d PC12 cells within 20 min that could be increased 5- to 8-fold by P together with TNFalpha. A peptide inhibitor of JNK1 abrogated P enhancement of TNFalpha-mediated dPC12 death but had only a minimal effect on cell death by TNFalpha alone. Inhibition of caspase-8 activation reduced death induced by TNFalpha alone but was much less effective for P+TNF. P alone did not activate caspase-8. E increased estrogen receptor alpha (ERalpha) and Bcl-xL expression and all but abolished TNFalpha receptor 1 (TNFR1) expression. P decreased ERalpha and Bcl-xL expression and doubled TNFR1 expression. These data suggest that P regulates apoptosis or survival through augmentation of JNK signaling and altered TNFR1 expression, whereas E mainly affects the expression of BCL-xL, TNFR1, and ERalpha.
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D016716:PC12 Cells; D011374:Progesterone / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051020:bcl-X Protein
D015703:Antigens, CD; D000970:Antineoplastic Agents; C494813:Bcl2l1 protein, rat; D047628:Estrogen Receptor alpha; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D011374:Progesterone; D004958:Estradiol; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases