Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases

TNF alpha is a pleiotropic cytokine that induces either cell proliferation or cell death. Inhibition of NF-kappa B activation increases susceptibility to TNF alpha-induced death, concurrent with sustained JNK activation, an important contributor to the death response. Sustained JNK activation in NF-kappa B-deficient cells was suggested to depend on reactive oxygen species (ROS), but how RIDS affect JNK activation was unclear. We now show that TNF alpha-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 TNF alpha-mediated fulminant liver failure without affecting liver regeneration.