reply: Kinase regulation in inflammatory response

Ozes et al . reply Delhase et al. take issue with our claim1 that Akt induces activation of NF-κB by phosphorylating IKKα, contending that IKKα plays no role in the activation by TNF of NF-κB, and consequently that Akt could not affect NF-κB through IKKα. They point out that Hu et al.2 have shown that cells deficient in IKKα have normal TNF-induced NF-κB activity, but this has been refuted by Li et al.3, who reported significant reduction of TNF-induced NF-κB in IKKα-deficient cells. Indeed, the observations of Hu et al.2 show that degradation of IκBα is diminished in cells from IKKα-deficient mice and are therefore not consistent with the conclusion that IKKα plays no role in TNF induction of NF-κB. Furthermore, deficiency of IKKβ only partially impairs TNF-induced NF-κB activation4,5, which reserves a role for IKKα in this pathway. Others5,6,7 have shown that activation of the IKK complex is dependent on the kinase activity of IKKα to activate IKKβ. Thus, strong evidence supports a role for IKKα in TNF induction of NF-κB.