TableEdit

Koski, CL, Hila, S and Hoffman, GE (2004) Regulation of cytokine-induced neuron death by ovarian hormones: involvement of antiapoptotic protein expression and c-JUN N-terminal kinase-mediated proapoptotic signaling. Endocrinology 145:95-103

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.

PubMed Online version:10.1210/en.2003-0803

Animals; Antigens, CD/metabolism; Antineoplastic Agents/pharmacology; Apoptosis/drug effects; Apoptosis/physiology; Caspase 8; Caspase 9; Caspases/metabolism; Cell Survival/drug effects; Cell Survival/physiology; Estradiol/pharmacology; Estrogen Receptor alpha; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases/metabolism; Nerve Growth Factor/pharmacology; Neurons/cytology; Neurons/drug effects; PC12 Cells; Progesterone/pharmacology; Proto-Oncogene Proteins c-bcl-2/metabolism; Rats; Receptors, Estrogen/metabolism; Receptors, Tumor Necrosis Factor/metabolism; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction/drug effects; Signal Transduction/physiology; Time Factors; Tumor Necrosis Factor-alpha/pharmacology; bcl-X Protein