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Delineation of the Signaling Pathways Involved in Glucocorticoid-Induced and Spontaneous Apoptosis of Rat Thymocytes

Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health (C.L.M., J.A.C.), Research Triangle Park, North Carolina 27709; and Curriculum in Toxicology, University of North Carolina (C.L.M.), Chapel Hill, North Carolina 27599

Address all correspondence and requests for reprints to: Dr. John A. Cidlowski, P.O. Box 12233 MD E2–02, Research Triangle Park, North Carolina 27709. E-mail: cidlowski{at}niehs.nih.gov

In primary rat thymocytes, both glucocorticoids and the withdrawal of in vivo survival factors elicit apoptosis. In this study we wanted to determine whether distinct pathways leading to apoptosis are engaged by these two stimuli. To address this question, we conducted a multiparametric analysis of cell viability, DNA fragmentation, activation of caspase-3-like activity, cell shrinkage, the loss of mitochondrial membrane potential, and externalization of phosphatidylserine in the absence and presence of protein and RNA synthesis. The role of caspase activity was also examined in both glucocorticoid- and survival factor withdrawal-induced cell death. We show that glucocorticoid-induced, but not spontaneous, loss of viability is dependent upon macromolecular synthesis and caspase activity. Furthermore, glucocorticoid-induced phosphatidylserine externalization and cell shrinkage are dependent upon gene regulation and caspase activity, whereas these features manifest independently of gene regulation and caspase activity in spontaneous death. In contrast, the loss of mitochondrial membrane potential was dependent upon macromolecular synthesis only in glucocorticoid-induced death and was independent of caspases in both spontaneous and dexamethasone-induced death. These results suggest that thymocytes can die by a caspase-independent mechanism and that a major difference between glucocorticoid- and survival factor deprivation-induced death is the dependence on gene expression.

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