Reactive Oxygen Species Promote TNF(alpha)-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 ROS 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 H2O2 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.