Antioxidants differentially regulate activation of nuclear factor-kappa B, activator protein-1, c-jun amino-terminal kinases, and apoptosis induced by tumor necrosis factor: evidence that JNK and NF-kappa B activation are not linked to apoptosis.
Tumor necrosis factor (TNF) is known to mediate its signaling through generation of reactive oxygen species (ROS), but the type of TNF signal regulated by ROS and the nature of the ROS species involved are not fully understood. In this report, we investigated the effect of various superoxide radical quenchers--pyrrolidine dithiocarbamate (PDTC), N-acetyl-L-cysteine (NAC), and glutathione (GSH)--an hydroxyl radical quencher (mannitol), and lipid peroxide quenchers--butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA)--on TNF-induced activation of nuclear transcription factors-kappa B (NF-kappa B) and activator protein-1 (AP-1), c-jun amino-terminal kinase (JNK), and apoptosis in human monocytic U937 cells. TNF-induced NF-kappa B activation was inhibited by both superoxide and lipid peroxide quenchers but potentiated by an hydroxyl radical quencher. In contrast, none of the radical quenchers had any significant effect on TNF-induced AP-1 activation. TNF-induced JNK activation, similar to NF-kappa B, was inhibited by both superoxide and lipid peroxide quenchers but potentiated by hydroxyl radical quencher. TNF-induced activation of caspase activity was blocked by all three types of quenchers. TNF cytotoxicity, however, was potentiated by superoxide radical quenchers and suppressed by hydroxyl radical and lipid peroxide quenchers. Overall, these results suggest that hydroxyl radicals mediate TNF-induced apoptosis but not activation of NF-kappa B, AP-1, and JNK; superoxide radicals mediate NF-kappa B and JNK activation but potentiate apoptosis; and lipid peroxides are required for all the signals induced by TNF.
Cytokine Research Laboratory, Department of Molecular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
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A
Shrivastava
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Aggarwal
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D017665:Hydroxyl Radical / Q000037:antagonists & inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D015227:Lipid Peroxidation / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D013481:Superoxides / Q000037:antagonists & inhibitors; D013859:Thiocarbamates / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity; D020298:U937 Cells
D000975:Antioxidants; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D002084:Butylated Hydroxytoluene; D002083:Butylated Hydroxyanisole; C020972:pyrrolidine dithiocarbamic acid; D017665:Hydroxyl Radical; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione; D000111:Acetylcysteine