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Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2282-2296
Dexamethasone-Induced Thymocyte Apoptosis: Apoptotic Signal
Involves the Sequential Activation of Phosphoinositide-Specific
Phospholipase C, Acidic Sphingomyelinase, and Caspases
Maria Grazia Cifone,
Graziella Migliorati,
Raffaella Parroni,
Cristina Marchetti,
Danilo Millimaggi,
Angela Santoni, and
Carlo Riccardi
From the Department of Experimental Medicine, University of
L'Aquila, L'Aquila, Italy; Department of Experimental Medicine and
Pathology, University La Sapienza, Rome, Italy; and Department of
Clinical and Experimental Medicine, University of Perugia, Perugia,
Italy.
Glucocorticoid hormones (GCH) have been implicated as regulators of
T-lymphocyte growth and differentiation. In particular, it has been
reported that GCH can induce thymocyte apoptosis. However, the
molecular mechanisms responsible for this GCH-induced death have not
been clarified. In this work, the biochemical events associated with
apoptosis induced by Dexamethasone (Dex), a synthetic GCH, in normal
mouse thymocytes, have been analyzed. Results indicate that Dex-induced
thymocyte apoptosis is attributable to an early ceramide generation
caused by the activation of an acidic sphingomyelinase (aSMase).
Caspase activity plays a crucial role in Dex-induced apoptosis and is downstream the aSMase activation in that inhibition of
the early ceramide generation inhibits caspase activation and thymocyte
death. Moreover, Dex treatment rapidly induces diacylglycerol (DAG)
generation, through a protein kinase C (PKC) and
G-protein-dependent phosphatidylinositol-specific phospholipase C
(PI-PLC), an event which precedes and is required for aSMase
activation. Indeed, PI-PLC inhibition by U73122 totally prevents
Dex-induced aSMase activity, ceramide generation, and consequently,
caspase activation and apoptosis. All these effects require Dex
interaction with GCH receptor (GR), are countered by the GR antagonist
RU486, and precede the GCH/GR-activated transcription and protein
synthesis. These observations indicate that GCH activates thymocyte
death through a complex signaling pathway that requires the sequential activation of different biochemical events.
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