NF-κB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKKβ

IKK beta-dependent NF-kappa B activation plays a key role in innate immunity and inflammation, and inhibition of IKK beta has been considered as a likely anti-inflammatory therapy. Surprisingly, however, mice with a targeted IKK beta deletion in myeloid cells are more susceptible to endotoxin-induced shock than control mice. Increased endotoxin susceptibility is associated with elevated plasma IL-1 beta as a result of increased pro-IL-1 beta processing, which was also seen upon bacterial infection. In macrophages enhanced pro-IL-1 beta processing depends on caspase-1, whose activation is inhibited by NF-kappa B-dependent gene products. In neutrophils, however, IL-1 beta secretion is caspase-1 independent and depends on serine proteases, whose activity is also inhibited by NF-kappa B gene products. Prolonged pharmacologic inhibition of IKK beta also augments IL-1 beta secretion upon endotoxin challenge. These results unravel an unanticipated role for IKK beta-dependent NF-kappa B signaling in the negative control of IL-1 beta production and highlight potential complications of long-term IKK beta inhibition.