The Role of Reactive Nitrogen Species (RNS) in the Activation of Nuclear Factor Kappa B (NFkB) and Its Implications for Biological Systems: The Question of Balance

  • Predrag S. Ljubuncic
  • Marina Bar-Shai
  • Abraham Z. Reznick

The members of redox-sensitive transcription factor nuclear kappa enhancer binding protein (NFkB) contain conserved REL-homology domain (RHD) responsible for DNA binding, dimerization, nuclear translocation as well as interaction with IkB inhibitory proteins. These inhibitory IkBs bind to NfkB and block its nuclear import and transcriptional activity. NFkB pathway plays a central role in the regulation of diverse cellular processes by regulating expression of target genes involved in inflammation, immunity and cell survival. The IKKβand IKKγ subunits of the IkB kinase (IKK) signalosome are required for the rapid NFkB canonical activation that leads to the IkB phosphorylation and its subsequent release from NFkB heterodimmers RelA/ p50 which is then translocated into the nucleus. In contrast, a subset of TNF family members function as biphasic activators of NFkB by activating canonical NFkB pathway as well as noncanoncial route of activation involving protein kinase NIK, phosphorylation of IKKB and the activation of RelB/p52 heterodimers. Nitrogen oxide (NO) and peroxynitrite (ONOO) are highly active reactive nitrogen species (RNS); at low concentrations (5–20μM), NO has been found to induce rapidly NFkB in the canonical activation pathway in L8 rat myoblasts. At high concentration (above 100μM), NO has been shown to have inhibitory effect on NFkB activation. The role of peroxynitrite remains contentious: Authentic peroxynitrite and its donors (5–100μM) are reported to activate NFkB in a noncanonical pathway in skeletal myocytes, for example by tyrosine nitration of IkBα on the expense of its serine phosphorylation and lack of degradation. This finally results in a prolonged nontransient activation of NFkB. Other works observed peroxynitrite induced inhibition of IKKα and concomitant phosphorylation of NFkB-inducing kinase (NIK) and IKKα in cardiac and endothelial cell lines, implying peroxynitrite may induce another noncanonical NFkB activation pathway via IKKα. Thus, this chapter summarizes results of studies concerning the role of RNS and RNS-generating compounds in NFkB signaling. The use of the different experimental models and cell types and the effects of exposure time, RNS concentrations and availability (extracellular vs. intracellular) as well as the significance of the redox state of the cells in the process of NFkB activation, are discussed and the implications for biological systems are also presented.


NFkB nitric oxide peroxynitrite nitrosylation nitration oxidation disease 


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Copyright information

© Springer Science + Business Media B.V 2008

Authors and Affiliations

  • Predrag S. Ljubuncic
    • 1
  • Marina Bar-Shai
    • 1
  • Abraham Z. Reznick
    • 1
  1. 1.Department of Anatomy and Cell BiologyTechnion-Israel Institute of TechnologyIsrael

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