NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta |
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Authors: | Greten Florian R Arkan Melek C Bollrath Julia Hsu Li-Chung Goode Jason Miething Cornelius Göktuna Serkan I Neuenhahn Michael Fierer Joshua Paxian Stephan Van Rooijen Nico Xu Yajun O'Cain Timothy Jaffee Bruce B Busch Dirk H Duyster Justus Schmid Roland M Eckmann Lars Karin Michael |
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Institution: | Second Department of Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 Germany. florian.greten@lrz.tum.de |
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Abstract: | IKKbeta-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. |
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