NF-kappa B activation by tumour necrosis factor requires the Akt serine-threonine kinase

Activation of the nuclear transcription factor NF-kappa B by inflammatory c ytokines requires the successive action of NF-kappa B-inducing kinase (NIK) and an I kappa B-kinase (IKK) complex composed of IKK alpha and IKK beta(1 -5). Here we show that the Akt serine-threonine kinase(6) is involved in th e activation of NF-kappa B by tumour necrosis factor (TNF). TNF activates p hosphatidylinositol-3-OH kinase (PI(3)K) and its downstream target Akt (pro tein kinase B). Wortmannin (a PI(3)K inhibitor), dominant-negative PI(3)K o r kinase-dead Akt inhibits TNF-mediated NF-kappa B activation. Constitutive ly active Akt induces NF-kappa B activity and this effect is blocked by dom inant-negative NIK. Conversely, NIK activates NF-KB and this is blocked by kinase-dead Akt. Thus, both Akt and NIK are necessary for TNF activation of NF-kappa B. Akt mediates IKKa phosphorylation at threonine 23. Mutation of this amino acid blocks phosphorylation by Akt or TNF and activation of NF- kappa B. These findings indicate that Akt is part of a signalling pathway t hat is necessary for inducing key immune and inflammatory responses.