The Nuclear Factor κB pathway: A link to the immune system in the radiation response

Exposure to ionizing radiation modulates immune responses in a complex dose-dependent pattern, with possible anti-inflammatory effects in the low dose range, expression of pro-inflammatory cytokines at moderate doses and immunosuppression after exposure to higher doses due to precursor cell death together with concomitant exacerbated innate immune responses. A central regulator in the immune system is the transcription factor Nuclear Factor kappa B (NF-kappa B). NF-kappa B is involved in the regulation of cellular survival, immune responses and inflammation, resulting in eminent importance in cancerogenesis. After exposure to ionizing radiation, NF-kappa B activation is initially triggered by ATM which is activated by DNA double strand breaks. Together with the NF-kappa B essential modulator (NEMO), it serves as a nucleoplasmic shuttle. The pathway converges with the classical NF-kappa B pathway at I kappa B kinase (IKK) complex activation. Resulting cytokine expression can activate NF-kappa B in a positive feed forward loop. Danger signals released from dying cells can activate NF-kappa B via Toll-like receptors (TLRs). The resulting immune activation can be beneficial or detrimental. In the low dose range, pro- and anticancerogenic effects are possible. In the radiotherapy-relevant dose range, tolerogenic immune responses should be avoided, and an antitumor immune response might be supported by TLR agonists activating NF-kappa B. (C) 2015 Elsevier Ireland Ltd. All rights reserved.