ROS-mediated crosstalk between NF-κB and JNK upon TNFα stimulation

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Whereas the relevance of ROS in TNF-induced NF-κB activation is still controversial, their importance in mediating the cross-talk between JNK and NF-κB activation upon TNF induction is now well characterized. As mentioned above, TNFR1 ligation triggers activation of both NF-κB and JNK signalling, two pathways having opposite biological roles. Even if that research area is still a matter of controversy, one can say by large that JNK activation promotes apoptosis via the mitochondrial-dependent pathway [112], whereas NF-κB activation promotes cell survival by upregulating the expression of antiapoptotic members of the Bcl2 family and caspase inhibitors [113]. It has also been reported that NF-κB can inhibit apoptosis by down-regulating JNK activation. Tang et al. and De Smaele et al. have demonstrated that TNF induces prolonged JNK activation in NF-κB activation-deficient cells (p65/RelA and IKKβ knockouts and cell expressing degradation-resistant IκBα), which in turn promotes apoptosis, suggesting that TNF-induced NF-κB target genes block JNK activation [114, 115]. In that respect, they identified GADD45β (growth arrest and DNA damage-inducing protein 45β) and XIAP (X chromosome-linked IAP) as capable of inhibiting JNK signalling by inactivating MEKK7 (which triggers the JNK pathways) [116] and inhibiting caspase activation, respectively. However, analysis of Gadd45β^-/- and Xiap^-/- fibroblasts failed to reveal changes in the kinetics of JNK activation, making the molecular mechanism by which NF-κB down-regulates JNK quite controversial [117, 118]. Recently, this mechanism was more deeply delineated and the crucial role of ROS has emerged. In fact, several laboratories have independently reported that NF-κB down-regulates JNK activation by suppressing TNF-induced ROS accumulation [119-122] (reviewed in [123, 124]). They showed that TNF-induced ROS production is responsible for sustained JNK activation in NF-κB-activation deficient cells, whereas wild-type cells exhibited neither ROS production nor sustained JNK activation upon TNF challenge. Moreover, prolonged JNK activation is inhibited by pre-treatment of NF-κB-defective cells with the antioxidants BHA or NAC, suggesting that ROS are key messengers of prolonged JNK activation after TNF induction. The molecular mechanism by which ROS activate JNK has been recently reported [122]. Indeed, ROS inactivate MAP kinase phosphatases (MKPs, which are known to suppress JNK activation) by oxidizing critical residues in their phosphatase domain, which lead to prolonged JNK activation (Figure 5). Moreover, oxidized MKPs are rapidly degraded by the ubiquitin-proteasome pathway. Several data may explain how NF-κB, when present, inhibits TNF-induced ROS accumulation. For example, a number of antioxidant enzymes like MnSOD were reported to be expressed in response to TNF in an NF-κB-dependent fashion [125], which can explain a more efficient ROS clearance after TNF induction in wild-type cells, and a sustained ROS production in NF-κB-defective cells.