Author/Authors :
Florian R. Greten، نويسنده , , Melek C. Arkan، نويسنده , , Julia Bollrath، نويسنده , , Li-Chung Hsu، نويسنده , , Jason Goode، نويسنده , , Cornelius Miething، نويسنده , , Serkan I. G?ktuna، نويسنده , , Michael Neuenhahn، نويسنده , , Joshua Fierer، نويسنده , , Stephan Paxian، نويسنده , , Nico van Rooijen، نويسنده , , Yajun Xu، نويسنده , , Timothy Ocain، نويسنده , , Bruce B. Jaffee، نويسنده , , Dirk H. Busch، نويسنده , , Justus Duyster، نويسنده , , Roland M. Schmid، نويسنده , , Lars Eckmann، نويسنده , , Michael Karin، نويسنده ,
Abstract :
IKKβ-dependent NF-κB activation plays a key role in innate immunity and inflammation, and inhibition of IKKβ has been considered as a likely anti-inflammatory therapy. Surprisingly, however, mice with a targeted IKKβ deletion in myeloid cells are more susceptible to endotoxin-induced shock than control mice. Increased endotoxin susceptibility is associated with elevated plasma IL-1β as a result of increased pro-IL-1β processing, which was also seen upon bacterial infection. In macrophages enhanced pro-IL-1β processing depends on caspase-1, whose activation is inhibited by NF-κB-dependent gene products. In neutrophils, however, IL-1β secretion is caspase-1 independent and depends on serine proteases, whose activity is also inhibited by NF-κB gene products. Prolonged pharmacologic inhibition of IKKβ also augments IL-1β secretion upon endotoxin challenge. These results unravel an unanticipated role for IKKβ-dependent NF-κB signaling in the negative control of IL-1β production and highlight potential complications of long-term IKKβ inhibition.
