Activation of the nuclear transcription factor NF-κB by inflammatory cytokines requires the successive action of NF-≃ B-inducing kinase (NIK) and an IκB-kinase (IKK) complex composed of IKKα and IKKβ. Here we show that the Akt serine-threonine kinase is involved in the activation of NF-κB by tumour necrosis factor (TNF). TNF activates phosphatidylinositol-3-OH kinase (PI(3)K) and its downstream target Akt (protein kinase B). Wortmannin (a PI(3)K inhibitor), dominant-negative PI [3)K or kinase-dead Akt inhibits TNF- mediated NF-κB activation. Constitutively active Akt induces NF-κB activity and this effect is blocked by dominant-negative NIK. Conversely, NIK activates NF-κB and this is blocked by kinase-dead Akt. Thus, both, Akt and NIK are necessary for TNF activation of NF-κB. Akt mediates IKKα phosphorylation at threonine 23. Mutation of this amino acid blocks phosphorylation by Akt or TNF and activation of NF-κB. These findings indicate that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses.
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