Oxidative Stress and Nuclear Factor-kappaB Activation: a Reassessment of the Evidence in the Light of Recent Discoveries

Nuclear factor-kappaB (NFKB) is a transcription factor with a pivotal role in inducing genes involved in physiological processes as well as in the response to injury and infection. A model has been proposed whereby the diverse agents that activate NFkappaB do so by increasing oxidative stress within the cell. Activation of NFkappaB involves the phosphorylation and subsequent degradation of an inhibitory protein, IKB, and recently many of the proximal kinases and adaptor molecules involved in this process have been elucidated. Additionally, we now understand in detail the NFkappaB activation pathway from cell membrane to nucleus for interleukin-1 (IL-1) and tumour necrosis factor (TNF). This review revisits the evidence for the oxidative stress model in light of these recent findings, and finds little in the new information to rationalise or justify a central role for oxidative stress in NF-kappaB activation. We demonstrate that much of the evidence for the involvement of oxidative stress is either specific to a stimulus in a particular cell line or open to reinterpretation. In particular, the activation of NFkappaB by hydrogen peroxide is cell-specific and distinct from physiological activators such as IL-1 and TNF, while inhibition by antioxidants, also found to be cell- and stimulus-specific, can involve diverse and unexpected targets which may be distinct from redox modulation. We conclude that in most cases the role of oxidative stress in NF-kappaB activation is at best facilitatory rather than causal, if a role exists at all. In addition, other evidence suggests a role for lipid peroxides in pathways where such a role exists. In future, when a role for oxidative stress in a pathway is postulated, the challenge will be to show which particular kinases or adaptor molecules, if any, are redox-modulated.