17-beta-estradiol induces an inhibitor of active caspases

We have shown previously that caspase-6 activity is lethal to human neurons (LeBlanc et al., 1999; Zhang et al., 2000). Here we find that 17-beta -est radiol but not 17-alpha -estradiol prevents caspase-6-mediated neuronal cel l death. 17-beta -estradiol-treated neuronal extracts directly inhibit reco mbinant active caspase-6, caspase-3, caspase-7, and caspase-8 in vitro. We conclude that 17-beta -estradiol induces a caspase inhibitory factor (CIF) that is preventing neuronal apoptosis. The induction of CIF occurs within 1 0 min of 17-beta -estradiol exposure to neurons, does not require de novo p rotein synthesis, and involves mitogen-activated protein kinase activation. The effect is antagonized by the estrogen receptor antagonist tamoxifen. I n contrast, 17-beta -estradiol does not induce CIF or prevent caspase-media ted cell death in cultured astrocytes. CIF does not act through oxidation o f the caspase active site. CIF activity copurifies with proteins of between 12 and 14 kDa in size. Our results indicate that 17-beta -estradiol induce s an inhibitor of active caspases through a receptor-mediated nongenomic pa thway and provide an additional mechanism for the neuroprotective action of 17-beta -estradiol that is likely highly relevant to the understanding of the role of estrogen against Alzheimer's disease.