Differential requirement for NF-κB-inducing kinase in the induction of NF-κB by IL-1β, TNF-α, and Fas

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Abstract
In this study, we examined the role of the nuclear factor-κB (NF-κB)-inducing kinase (NIK) in distinct signaling pathways leading to NF-κB activation. We show that a dominant-negative form of NIK (dnNIK) delivered by adenoviral (Ad5dnNIK) vector inhibits Fas-induced IκBα phosphorylation and NF-κB-dependent gene expression in HT-29 and HeLa cells. Interleukin (IL)-1β- and tumor necrosis factor-α (TNF-α)-induced NF-κB activation and κB-dependent gene expression are inhibited in HeLa cells but not in Ad5dnNIK-infected HT-29 cells. Moreover, Ad5dnNIK failed to sensitize HT-29 cells to TNF-α-induced apoptosis at an early time point. However, cytokine- and Fas-induced signals to NF-κB are finally integrated by the IκB kinase (IKK) complex, since IκBα phosphorylation, NF-κB DNA binding activity, and IL-8 gene expression were strongly inhibited in HT-29 and HeLa cells overexpressing dominant-negative IKKβ (Ad5dnIKKβ). Our findings support the concept that cytokine signaling to NF-κB is redundant at the level of NIK. In addition, this study demonstrates for the first time the critical role of NIK and IKKβ in Fas-induced NF-κB signaling cascade.