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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-06-1779.
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Blood, 15 January 2003, Vol. 101, No. 2, pp. 585-593
IMMUNOBIOLOGY
Dexamethasone-induced apoptosis of thymocytes: role of
glucocorticoid receptor-associated Src kinase and caspase-8
activation
Maria Cristina Marchetti,
Barbara Di Marco,
Grazia Cifone,
Graziella Migliorati, and
Carlo Riccardi
From the Department of Clinical and Experimental
Medicine, Pharmacology Section, University of Perugia, and the
Department of Experimental Medicine, University of L'Aquila,
Italy.
Glucocorticoid hormones (GCHs) regulate normal and neoplastic
lymphocyte development by exerting antiproliferative and/or apoptotic
effects. We have previously shown that dexamethasone (DEX)-activated
thymocyte apoptosis requires a sequence of events including interaction
with the glucocorticoid receptor (GR), phosphatidylinositol-specific phospholipase C (PI-PLC), and acidic sphingomyelinase (aSMase) activation. We analyzed the mechanisms of GCH-activated apoptosis by
focusing on GR-associated Src kinase, cytochrome c release, and caspase-8, -9, and -3 activation. We show here that PI-PLC binds to
GR-associated Src kinase, as indicated by coimmunoprecipitation experiments. Moreover, DEX treatment induces PI-PLC
phosphorylation and activation. DEX-induced PI-PLC phosphorylation,
activation, and apoptosis are inhibited by PP1, a Src kinase inhibitor,
thus suggesting that Src-mediated PI-PLC activation is involved
in DEX-induced apoptosis. Caspase-9, -8, and -3 activation and
cytochrome c release can be detected 1 to 2 hours after DEX
treatment. Caspase-9 inhibition does not counter cytochrome c
release, caspase-8 and caspase-3 activation, and apoptosis.
Caspase-8 inhibition counters cytochrome c release,
caspase-9 and caspase-3 activation, and apoptosis, thus suggesting that
caspase-8 inhibitor can directly inhibit caspase-9 and/or that
DEX-induced caspase-8 activation is upstream to mitochondria and can
regulate caspase-3 directly or through cytochrome c release
and the consequent caspase-9/caspase-3 activation. DEX-induced
caspase-8 activation, like ceramide-induced caspase-8
activation, correlates with the formation of Fas-associated death domain protein (FADD)/caspase-8 complex. Caspase-8
activation is countered by the inhibition of macromolecular synthesis
and of Src kinase, PI-PLC, and aSMase activation, suggesting it is downstream in the DEX-activated apoptotic pathway of thymocytes.
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