NF-kappaB meets ROS: an 'iron-ic' encounter

Since becoming abundant in the atmosphere approximately 2.3 billion years ago, oxygen has been a defining element for life on our planet. One needs not be a biologist to know the importance of oxygen for sustaining life – termed in fact ‘aerobic’ life. Our body is built around the need to maximize exploitation of oxygen for the production of energy. The respiratory and cardiovascular systems are exemplary illus- trations of this need. Like all good things, however, oxygen can also be extremely harmful. Its original accumulation on Earth caused the extinction of most existing life forms, defenseless against oxidative damage. Even a layperson is aware of this potential toxicity of oxygen. Indeed, nowadays antioxidants are among the most heavily advertised dietary supplements on the market. Yet, it would surprise most to know that the potent reactivity of oxygen and its products – so- called reactive oxygen species (ROS) – is purposefully used by nature to transduce signals that actively trigger cell suicide or programmed cell death (PCD), as well as other biological responses. One pathway that seems to fully exploit this reactivity of ROS for inflicting cell death is that initiated by TNFa engagement of TNF-R1, a pathway that plays a central role in immunity, inflammation, cell growth, cell death and differentiation.1–3 This pathway is also crucial for pathogen- esis of human diseases such as cancer and chronic inflammatory conditions, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD).1,3,4 Not surprisingly, it has been the subject of intense investigation for over one century.1 TNFa-induced killing is antagonized by activation of NF-kB-family transcription factors3,4 – which act as master coordinators of immune and inflammatory responses.4 The prosurvival activity of NF-kB is also crucial for lymphocyte development, tumorigenesis and cancer chemoresistance.4,5 In recent years, remarkable progress has been made in our understanding of the mechanisms governing TNFa-induced death and NF-kB-mediated survival.3,4 As it turns out, ROS have now taken center stage in the intricate multitude of players that control cell fate downstream of TNF-R1, as they appear to be at an obligatory crossroads of the opposing pathways for life and death elicited by stimulation of this receptor. Indeed, now there is hope that this new under- standing of TNF-R-induced pathways may lead to the development of new approaches for treatment of widespread human diseases.