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 AKT or IB kinase mutant, IKKT23A, containing a mutation in a functional AKT phosphorylation site, shown previously to be important for NFB activation, completely abrogated IL-6 promoter activation in response to IL-1. However, mutation of the consensus NFB 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 on the NFB inducing kinase (NIK) phosphorylation sites Ser 176 /Ser 180 and on the Thr 23 site, and although phosphorylation of IKKT23 is inhibited both by LY294002 and wortmannin, phosphorylation of Ser 176 /Ser 180 is not. Neither inhibition of PI 3-kinase/AKT nor IKKT23A overexpression affected IB degradation in response to IL-1. Only partial inhibition by dominant-negative AKT and no inhibitory effect of IKKT23A was observed on an IL-6 promoter-specific NFB 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/IKKT23 upstream of AP-1. This novel pathway is a parallel pathway to the PI 3-kinase/AKT upstream of NFB and both are involved in IL-6 gene transcription in response to IL-1.