ATP-induced apoptosis of thymocytes is mediated by activation of P2 X 7 receptor and involves de novo ceramide synthesis and mitochondria.
Thymocytes were reported to undergo apoptosis in the presence of extracellular ATP through the activation of the purinergic receptors P2 X 1R, P2 X 7R or both. We investigated the identity of the P2 X R and the signaling pathways involved in ATP-mediated apoptosis. Apoptosis elicited by ATP was prevented by inhibition of P2 X 7R, or in thymocytes bearing a mutated P2 X 7R, and reproduced with a P2 X 7R agonist, but not with a P2 X 1R agonist. Stimulation of thymocytes with either ATP or a P2 X 7R agonist was found to stimulate a late de novo ceramide synthesis and mitochondrial alterations. Inhibition of either processes attenuated apoptosis. Interestingly, stimulation with either ATP or a P2 X 1R agonist induced an early ceramide accumulation and a weak caspases-3/7 activation that did not lead to apoptosis. In conclusion, de novo ceramide generation and mitochondrial alterations, both resulting from P2 X 7R activation, were implicated in ATP-induced thymocyte apoptosis.
Lépine
S
S
Biomembranes et Messagers Cellulaires, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8619, Université Paris XI-Orsay, France.
Le Stunff
H
H
Lakatos
B
B
Sulpice
J C
JC
Giraud
F
F
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D013110:Sphingosine / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*
D002518:Ceramides; C546469:P2rx7 protein, mouse; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D013110:Sphingosine