Reactive Oxygen Species Support Tumor Necrosis Factor-Mediated Programmed Cell Death

Michael Karin, Ph.D.
University of California San Diego
R37ES004151, P42ES010337, and R01ES006376

Background: Tumor necrosis factor alpha (TNFα) is a small intracellular protein that produces multiple effects in that it can be either a cell proliferation agent or an inducer of cell death. Nuclear factor kappa B (NFκB), a transcription factor, is a negative regulator of programmed cell death especially in response to TNFα. Preventing the activation of NFκB leads to TNFα-induced cell death along with sustained activation of Jun N-terminal kinase (JNK). In normal cells with NFκB, TNFα causes a fast but transient activation of JNK. However, in NFκB deficient cells, the JNK activation is dramatically extended leading to cell death. Reactive oxygen species, molecules such as hydrogen peroxide, have been suggested to be involved in the sustained JNK activation in the NFκB deficient cells; however the mechanism is unclear. It is likely that liver toxins or some viruses that cause acute liver failure do so through the inhibition of NFκB. These investigators wished to further understand how reduced NFκB activity leads to sustained JNK activation, accumulation of reactive oxygen molecules, and increased programmed cell death.

Advance: The new findings show that reactive oxygen species induced by TNFα oxidize and inhibit phosphatase enzymes that inactivate JNK by interacting with cysteine amino acids in the enzymes’ structures. This causes the sustained activation of JNK resulting in cell death. Additional experiments were conducted in which cell cultures and laboratory animals were treated with an antioxidant (butylated hydroxyanisole). The antioxidant prevented the accumulation of the reactive oxygen molecules, JNK phosphatase oxidation and subsequent inactivation, shortened the period of JNK activation, and thus prevented cell death.

Implications: These findings demonstrate that antioxidant treatment prevents TNFα-induced liver failure. The investigators propose that targeted antioxidants may provide an effective treatment for acute liver failure along with more chronic liver diseases such as viral hepatitis and cirrhosis.

Citation: Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell. 2005 Mar 11;120(5):649-61.