Greten, Florian RFlorian RGretenArkan, Melek CMelek CArkanBollrath, JuliaJuliaBollrathLI-CHUNG HSUGoode, JasonJasonGoodeMiething, CorneliusCorneliusMiethingGöktuna, Serkan ISerkan IGöktunaNeuenhahn, MichaelMichaelNeuenhahnFierer, JoshuaJoshuaFiererPaxian, StephanStephanPaxianVan Rooijen, NicoNicoVan RooijenXu, YajunYajunXuO'Cain, TimothyTimothyO'CainJaffee, Bruce BBruce BJaffeeBusch, Dirk HDirk HBuschDuyster, JustusJustusDuysterSchmid, Roland MRoland MSchmidEckmann, LarsLarsEckmannKarin, MichaelMichaelKarin2024-04-262024-04-262007-09-070092-8674https://scholars.lib.ntu.edu.tw/handle/123456789/642065IKKbeta-dependent NF-kappaB activation plays a key role in innate immunity and inflammation, and inhibition of IKKbeta has been considered as a likely anti-inflammatory therapy. Surprisingly, however, mice with a targeted IKKbeta deletion in myeloid cells are more susceptible to endotoxin-induced shock than control mice. Increased endotoxin susceptibility is associated with elevated plasma IL-1beta as a result of increased pro-IL-1beta processing, which was also seen upon bacterial infection. In macrophages enhanced pro-IL-1beta processing depends on caspase-1, whose activation is inhibited by NF-kappaB-dependent gene products. In neutrophils, however, IL-1beta secretion is caspase-1 independent and depends on serine proteases, whose activity is also inhibited by NF-kappaB gene products. Prolonged pharmacologic inhibition of IKKbeta also augments IL-1beta secretion upon endotoxin challenge. These results unravel an unanticipated role for IKKbeta-dependent NF-kappaB signaling in the negative control of IL-1beta production and highlight potential complications of long-term IKKbeta inhibition.enMOLIMMUNO | SIGNALINGjournal article10.1016/j.cell.2007.07.009178039132-s2.0-34548225362https://scholars.lib.ntu.edu.tw/handle/123456789/328935http://www.scopus.com/inward/record.url?eid=2-s2.0-34548225362&partnerID=MN8TOARS