IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation

Inflammation and innate immunity involve signalling pathways leading to the production of inflammatory mediators. Usually such responses are self-limiting, but aberrant resolution of inflammation results in chronic diseases(1). Much attention has focused on pro-inflammatory signalling but little is known about the mechanisms that resolve inflammation. The I kappa B kinase (IKK) complex contains two catalytic subunits, IKK alpha and IKK beta, and controls the activation of NF-kappa B transcription factors, which play a pivotal role in inflammation(2). Ample evidence indicates that IKK beta mediates NF-kappa B activation in response to pro-inflammatory cytokines and microbial products. IKK alpha regulates an alternative pathway important for lymphoid organogenesis(2), but the role of IKK alpha in inflammation is unknown. Here we describe a new role for IKK alpha in the negative regulation of macrophage activation and inflammation. IKK alpha contributes to suppression of NF-kappa B activity by accelerating both the turnover of the NF-kappa B subunits RelA and c-Rel, and their removal from pro-inflammatory gene promoters. Inactivation of IKK alpha in mice enhances inflammation and bacterial clearance. Hence, the two IKK catalytic subunits have evolved opposing but complimentary roles needed for the intricate control of inflammation and innate immunity.