Figure 4.

Molecular mechanisms activated after moderated doses of irradiation in tumor-associated macrophages (TAMs). Ionizing radiation (X-rays or γ-rays) induces DNA damage and elevated reactive oxygen species (ROS) content in cells. DNA repair machinery [such as ataxia telangiectasia mutated (ATM)] is activated by DNA damage and initiates the ubiquitination of NFκB essential modulator (NEMO), a subunit of the IKK complex. Therefore, ubiquinated NEMO can drive the activation of IKK complex in the cytoplasm. The degradation of IκB protein by the proteasome allows the release of p50–p65 nuclear factor kappa B (NFκB) in the cytoplasm. p50–p65 NFκB is then translocated into the nucleus and induces the transcription of pro-inflammatory genes, leading to the reprogramming of TAMs. ROS are also able to stimulate mitogen-activated protein kinase (MAPKs). Once phosphorylated, MAPKs also participate to the activation of NFκB and hence, to the transcription of pro-inflammatory genes.