title: P2X7 receptor-dependent cell death is modulated during murine T cell maturation and mediated by dual signaling pathways.
abstract: Extracellular ATP causes apoptosis and/or necrosis of the hemopoietic lineage through the activation of P2X7 receptors. In this study, we investigated P2X7 receptor-mediated cell death during murine T cell maturation. The expression level and activity of P2X7 receptors, as measured by induction of cell death and pore formation, were higher in splenocytes than thymocytes. Flow cytometric analysis revealed that cell shrinkage was induced by activation of the P2X7 receptor in murine lymphocytes and the responding cells were T cells. Splenic T cells were more responsive than their thymic counterpart. These observations indicate that the system of P2X7 receptor-mediated cell death in T cells could be modulated during T cell maturation. Furthermore, decreased extracellular Cl- suppressed ATP-induced cell shrinkage in splenocytes without inhibiting ERK1/2 phosphorylation, which is reported to mediate necrotic cell death. Treatment with U0126 (a MEK inhibitor) suppressed ATP-induced ERK1/2 phosphorylation without inhibiting cell shrinkage. Moreover, decreased extracellular Cl- and treatment with U0126 suppressed ATP-induced cell death. These observations indicate that the activation of P2X7 receptor leads to T cell death by two independent pathways, one of which is cell shrinkage dependent and the other of which involves the phosphorylation of ERK1/2. In conclusion, we demonstrate increasing P2X7 receptor activity during T cell maturation and the existence of two essential pathways in P2X7 receptor-mediated T cell death. Our findings suggest that ATP-induced cell death of peripheral T lymphocytes is important in P2X7 receptor-regulated immune responses.
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Tsukimoto
authors.forename: Machiko
authors.initials: M
authors.lastname: Maehata
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Harada
authors.forename: Akira
authors.initials: A
authors.lastname: Ikari
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Takagi
authors.forename: Masakuni
authors.initials: M
authors.lastname: Degawa
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation; D048430:Cell Shape; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases