Cellular oxidative stress and the control of apoptosis by wild-type p53, cytotoxic compounds, and cytokines.
Apoptosis induced by wild-type p53 or cytotoxic compounds in myeloid leukemic cells can be inhibited by the cytokines interleukin 6, interleukin 3, granulocyte-macrophage colony-stimulating factor, and interferon gamma and by antioxidants. The antioxidants and cytokines showed a cooperative protective effect against induction of apoptosis. Cells with a higher intrinsic level of peroxide production showed a higher sensitivity to induction of apoptosis and required a higher cytokine concentration to inhibit apoptosis. Decreasing the intrinsic oxidative stress in cells by antioxidants thus inhibited apoptosis, whereas increasing this intrinsic stress by adding H2O2 enhanced apoptosis. Induction of apoptosis by wild-type p53 was not preceded by increased peroxide production or lipid peroxidation and the protective effect of cytokines was not associated with a decrease in these properties. The results indicate that the intrinsic degree of oxidative stress can regulate cell susceptibility to wild-type p53-dependent and p53-independent induction of apoptosis and the ability of cytokines to protect cells against apoptosis.
Lotem
J
J
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Peled-Kamar
M
M
Groner
Y
Y
Sachs
L
L
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005452:Fluoresceins / Q000378:metabolism; D005720:Gamma Rays; D007951:Leukemia, Myeloid; D015227:Lipid Peroxidation; D018384:Oxidative Stress / Q000502:physiology*; D010545:Peroxides / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000975:Antioxidants; D016207:Cytokines; D005452:Fluoresceins; D010545:Peroxides; D016159:Tumor Suppressor Protein p53; C029569:diacetyldichlorofluorescein; D002083:Butylated Hydroxyanisole; D004317:Doxorubicin; D003513:Cycloheximide