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NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta.

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
Type
Published Article
Journal
Cell
Publisher
Elsevier
Publication Date
Sep 07, 2007
Volume
130
Issue
5
Pages
918–931
Identifiers
PMID: 17803913
Source
Medline
License
Unknown

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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