Involvement of ROS in NF-κB activation by IL-1β

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IL-1β is a potent pro-inflammatory cytokine that exerts its effects by binding to its receptor (IL1-R1) on the plasma membrane. This binding induces the recruitment to the receptor cytoplasmic tail of adaptator and effector proteins, including IL-1RacP, MyD88 and Tollip [90-92]. MyD88 then mediates the recruitment of the interleukin-1 receptor-associated kinase (IRAK) family members to the IL-1R [93], which, in turn, recruits TRAF6 [94]. Then TRAF6 recruits TAK1 that mediates phosphorylation of the IKK complex, a crucial step in NF-κB activation [95].  The redox dependence of NF-κB activation by IL-1β was first shown by Bonizzi et al. to be cell-type specific. These authors showed that ROS production was required for NF-κB activation by IL-1β in both lymphoid and monocytic cells, but not in epithelial cells [82]. Using specific inhibitors, they identified 5- lipoxygenase (5-LOX) as the main source of ROS after IL-1β induction in lymphoid cells. 5-LOX is the first enzyme of the leukotriene biosynthesis pathway; it catalyses the insertion of molecular oxygen on C-5 of arachidonic acid. In monocytic cells, the main source of ROS in IL-1β-induced NF-κB activation was shown to be the NADPH oxidase complex [96]. Although at that time no ROS-dependence in NF-κB activation by IL-1β was demonstrated in epithelial cells, an elegant recent study, carried out by Li et al., called this idea into question. They showed that in MCF7 epithelial cells, IL-1β stimulation induces MyD88-dependent endocytosis of IL-1R1, and that this event is required for the redox-dependent NF-κB activation. During this endocytosis, Nox2 (a phagocytic NADPH oxidase also expressed in non-phagocytic cells) is recruited to the endosomal compartment in a Rac1-dependent fashion. Rac1, a small GTPase, plays a key role in activating O₂·^- production by NADPH oxidases. O₂·^- is thus produced in the IL-R1/Nox2-containing endosomal compartment. O₂·^- spontaneously dismutates to H₂O₂, which diffuses outside the endosome. This local oxidative stress triggers a TRAF6 association with the receptor complex on the ligand-activated endosome, which leads to IKK and NF-κB activation (Figure 4) [97]. The same authors have also reported that H₂O₂-mediated regulation of NIK is important in IL-1β induction of NF-κB [98]. Since the role of NIK in NF-κB activation by classical inducers (such as TNFα or IL-1β) is very controversial (NIK^-/- Mefs display unimpaired signalling in response to TNFα or IL-1 β in terms of NF-κB activation [99]), these results must be interpreted cautiously.