Interleukin (IL) 1β induction of IL-6 is mediated by a novel phosphatidylinositol 3-kinase-dependent AKT/IκB kinase α pathway targeting activator protein-1

Here we describe a novel role for the phosphatidylinositol 3-kinase/AKT pathway in mediating induction of interleukin-6 (IL-6) in response to IL-1. Pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K) inhibited IL-6 mRNA and protein production. Overexpression of either dominant-negative AKTor I kappa Bkinase alpha mutant, IKK alpha T23A, containing a mutation in a functional AKT phosphorylation site, shown previously to be important for NF kappa B activation, completely abrogated IL-6 promoter activation in response to IL-1. However, mutation of the consensus NF kappa B site on the IL-6 promoter did not abrogate promoter activation by IL-1 in contrast to the AP-1 site mutation. IL-1 induces phosphorylation of IKK alpha on the NF kappa B inducing kinase (NIK) phosphorylation sites Ser(176)/Ser(180) and on the Thr(23) site, and although phosphorylation of IKK alpha T23 is inhibited both by LY294002 and wortmannin, phosphorylation of Ser(176)/Ser(180) is not. Neither inhibition of PI 3-kinase/AKT nor IKK alpha T23A overexpression affected I kappa B alpha degradation in response to IL-1. Only partial inhibition by dominant-negative AKT and no inhibitory effect of IKK alpha T23A was observed on an IL-6 promoter-specific NF kappa B site in contrast to significant inhibitory effects on the AP-1 site. Taken together, we have discovered a novel PI 3-kinase/AKT-dependent pathway in response to IL-1, encompassing PI 3-kinase/AKT/IKK alpha T23 upstream of AP-1. This novel pathway is a parallel pathway to the PI 3-kinase/AKT upstream of NF kappa B and both are involved in IL-6 gene transcription in response to IL-1.