Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.
TNFalpha is a pleiotropic cytokine that induces either cell proliferation or cell death. Inhibition of NF-kappaB activation increases susceptibility to TNFalpha-induced death, concurrent with sustained JNK activation, an important contributor to the death response. Sustained JNK activation in NF-kappaB-deficient cells was suggested to depend on reactive oxygen species (ROS), but how ROS affect JNK activation was unclear. We now show that TNFalpha-induced ROS, whose accumulation is suppressed by mitochondrial superoxide dismutase, cause oxidation and inhibition of JNK-inactivating phosphatases by converting their catalytic cysteine to sulfenic acid. This results in sustained JNK activation, which is required for cytochrome c release and caspase 3 cleavage, as well as necrotic cell death. Treatment of cells or experimental animals with an antioxidant prevents H(2)O(2) accumulation, JNK phosphatase oxidation, sustained JNK activity, and both forms of cell death. Antioxidant treatment also prevents TNFalpha-mediated fulminant liver failure without affecting liver regeneration.
Kamata
Hideaki
H
Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Honda
Shi-Ichi
S
Maeda
Shin
S
Chang
Lufen
L
Hirata
Hajime
H
Karin
Michael
M
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019556:COS Cells; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002522:Chlorocebus aethiops; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000201:enzymology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013434:Sulfenic Acids / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D000975:Antioxidants; D017382:Reactive Oxygen Species; D013434:Sulfenic Acids; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D048031:JNK Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases