Figure 18.

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.