Two examples of ROS involvement in cytokine-dependent NF-κB activation. (a) NF-κB activation by IL-1β. In some cells IL-1β induces MyD88-dependent endocytosis of IL-R1; during endocytosis Rac1 recruits NOX2 in the endosomal compartment. NOX2 activation generates superoxide that spontaneously dismutates into H2O2, which then diffuses in the cytoplasm and triggers TRAF6 association with the ligand-receptor complex on the endosome, leading finally to NF-κB activation. (b) NF-κB activation by LPS. NF-κB activation by LPS through TLR4 activation involves Myd88 recruitment, which links TLR-4 activation to IRAK and TRAF6, mediating NF-κB activation. The involvement of ROS is consequent to direct interaction, followed by the Rac1-mediated activation of TLR-4 by NOX4 (or another NOX isoform, depending on the target cells). At present it is uncertain whether H2O2 operates (as for IL-1) by triggering activation of TRAF6.