TAK1 is Critical for IκB Kinase-mediated Activation of the NF-κB Pathway

Cytokine treatment stimulates the IκB kinases, IKKα and IKKβ, which phosphorylate the IκB proteins, leading to their degradation and activation of NF-κB regulated genes. A clear definition of the specific roles of IKKα and IKKβ in activating the NF-κB pathway and the upstream kinases that regulate IKK activity remain to be elucidated. Here, we utilized small interfering RNAs (siRNAs) directed against IKKα, IKKβ and the upstream regulatory kinase TAK1 in order to better define their roles in cytokine-induced activation of the NF-κB pathway. In contrast to previous results with mouse embryo fibroblasts lacking either IKKα or IKKβ, which indicated that only IKKβ is involved in cytokine-induced NF-κB activation, we found that both IKKα and IKKβ were important in activating the NF-κB pathway. Furthermore, we found that the MAP3K TAK1, which has been implicated in IL-1-induced activation of the NF-κB pathway, was also critical for TNFα-induced activation of the NF-κB pathway. TNFα activation of the NF-κB pathway is associated with the inducible binding of TAK1 to TRAF2 and both IKKα and IKKβ. This analysis further defines the distinct in vivo roles of IKKα, IKKβ and TAK1 in cytokine-induced activation of the NF-κB pathway.