An antiinflammatory role for IKKβ through the inhibition of classical macrophage activation

The nuclear factor kappa B (NF-kappa B) pathway plays a central role in inflammation and immunity. In response to proinflammatory cytokines and pathogen-associated molecular patterns, NF-kappa B activation is controlled by I kappa B kinase (IKK)beta. Using Cre/lox-mediated gene targeting of IKK beta, we have uncovered a tissue-specific role for IKK beta during infection with group B streptococcus. Although deletion of IKK beta in airway epithelial cells had the predicted effect of inhibiting inflammation and reducing innate immunity, deletion of IKK beta in the myeloid lineage unexpectedly conferred resistance to infection that was associated with increased expression of interleukin (IL)-12, inducible nitric oxide synthase (NOS2), and major histocompatibility complex (MHC) class II by macrophages. We also describe a previously unknown role for IKK beta in the inhibition of signal transducer and activator of transcription (Stat)1 signaling in macrophages, which is critical for IL-12, NOS2, and MHC class II expression. These studies suggest that IKK beta inhibits the classically activated or M1 macrophage phenotype during infection through negative cross talk with the Stat1 pathway. This may represent a mechanism to prevent the over-exuberant activation of macrophages during infection and contribute to the resolution of inflammation. This establishes a new role for IKK beta in the regulation of macrophage activation with important implications in chronic inflammatory disease, infection, and cancer.