Oxidative stress attenuates Fas-mediated apoptosis in Jurkat T cell line through Bfl-1 induction.
Many types of mammalian cells produce ROS in response to many different stimuli to modulate a number of cellular functions, including apoptosis. However, the correlation between ROS and apoptosis remains controversial, and the mechanisms whereby ROS-induced signals are propagated to critical downstream targets remain largely undefined. Here, we demonstrate that hydrogen peroxide (H2O2) upregulates the expression of Bfl-1, an antiapoptotic member of the Bcl-2 family, and that this is responsible for the antiapoptotic activity of ROS. When Jurkat, human leukemic T cells, were pretreated with 100 microM H2O2 and then treated with anti-Fas antibody, apoptosis was impaired without change of cell surface Fas expression. An investigation of the expression patterns of Bcl-2 family genes revealed that H2O2 treatment induced Bfl-1 gene expression, but left other genes unchanged, and this Bfl-1 expression and H2O2 -induced antiapoptotic effect was inhibited by antioxidants or NF-kappaB inhibitor. In addition, an electromobility shift assay revealed that the p65/p50 subunits of NF-kappaB activated by H2O2 bound to a bfl-1 promoter. Neither the induction of Bfl-1 nor the antiapoptotic effect of H2O2 was detected in Bfl-1-knockdown Jurkat cell line containing Bfl-1 antisense (Bfl-1AS). These data indicate that oxidative stress induces the expression of Bfl-1 via NF-kappaB activation, and this early-response gene protects cells from Fas-mediated apoptosis. This may be a cellular survival mechanism of cells exposed to phagocytes-derived ROS.
Kim
Heejung
H
Department of Pathology, Tumor Immunity Medical Research Center and Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
Kim
Yong-Nyun
YN
Kim
Hyungsoo
H
Kim
Chul-Woo
CW
D000111:Acetylcysteine / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045304:Cytochromes c / Q000378:metabolism; D015870:Gene Expression; D019254:Genes, bcl-2 / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019169:Jurkat Cells; D015778:Minor Histocompatibility Antigens; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics*; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000975:Antioxidants; C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C411023:anti-Fas monoclonal antibody; D019014:fas Receptor; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D000111:Acetylcysteine