Tumor necrosis factor alpha-induced apoptosis in astrocytes is prevented by the activation of P2Y6, but not P2Y4 nucleotide receptors.
The physiological role of the uracil nucleotide-preferring P2Y(6) and P2Y(4) receptors is still unclear, although they are widely distributed in various tissues. In an effort to identify their biological functions, we found that activation by UDP of the rat P2Y(6) receptor expressed in 1321N1 human astrocytes significantly reduced cell death induced by tumor necrosis factor alpha (TNF alpha). This effect of UDP was not observed in non-transfected 1321N1 cells. Activation of the human P2Y(4) receptor expressed in 1321N1 cells by UTP did not elicit this protective effect, although both receptors were coupled to phospholipase C. The activation of P2Y(6) receptors prevented the activation of both caspase-3 and caspase-8 resulting from TNF alpha exposure. Even a brief (10-min) incubation with UDP protected the cells against TNF alpha-induced apoptosis. Interestingly, UDP did not protect the P2Y(6)-1321N1 cells from death induced by other methods, i.e. oxidative stress induced by hydrogen peroxide and chemical ischemia. Therefore, it is suggested that P2Y(6) receptors interact rapidly with the TNF alpha-related intracellular signals to prevent apoptotic cell death. This is the first study to describe the cellular protective role of P2Y(6) nucleotide receptor activation.
Kim
Seong G
SG
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bldg. 8A, Rm. B1A-19, National Institutes of Health, Bethesda, MD 20892-0810, USA.
Soltysiak
Kelly A
KA
Gao
Zhan-Guo
ZG
Chang
Tong-Shin
TS
Chung
Eunju
E
Jacobson
Kenneth A
KA
D017209:Apoptosis / Q000502:physiology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020011:Protective Agents / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014530:Uridine Diphosphate / Q000494:pharmacology
D020011:Protective Agents; D018048:Receptors, Purinergic P2; D014409:Tumor Necrosis Factor-alpha; C104749:purinoceptor P2Y4; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate