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

FR Greten, MC Arkan, J Bollrath, LC Hsu, J Goode… - Cell, 2007 - cell.com
FR Greten, MC Arkan, J Bollrath, LC Hsu, J Goode, C Miething, SI Göktuna, M Neuenhahn…
Cell, 2007cell.com
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 …
Summary
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.
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