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| Innate immunity: An unexpected role for NF- | |||||||||||
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The functional elimination of IKK
(inhibitor of nuclear factor-
B (NF-B) kinase-) — an effector of NF-B-mediated inflammation — makes mice more susceptible to endotoxin-induced shock because of an increase in the level of circulating interleukin-1.
The IKK (inhibitor of nuclear factor-B (NF-B) kinase-)-dependent activation of NF-B is central in the transcriptional control of acute and chronic inflammation. For this reason IKK inhibitors have been proposed as plausible anti-inflammatory drugs. However, in this study, Greten and colleagues challenge this view by showing that the targeted deletion of IKK in mouse myeloid cells or the pharmacological inhibition of IKK unexpectedly result in a greater susceptibility to endotoxin-induced shock and mortality, owing to increased levels of circulating interleukin-1 (IL-1) as a result of enhanced pro-IL-1 processing.
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To examine whether the inhibition of IKK would prevent septic shock, the authors generated mice with a targeted deletion of IKK in myeloid cells (termed IKK
mye mice), or used a previously characterized mouse mutant in which the systemic injection of the interferon (IFN)-inducer polyI:C results in IKK deletion in all IFN-responsive cells (termed IKK mice), and then challenged both mutant strains with endotoxin. Survival of both IKK and IKKmye mice after endotoxin challenge was shown to be reduced compared with control mice. This enhanced toxicity was the result of a marked increase in the levels of plasma IL-1, as shown by the complete or markedly improved protection that was conferred to IKKmye and IKK mice, respectively, after the administration of an IL-1-receptor antagonist. In addition, IKK mice exhibited neutrophilia, suggesting a role for NF-B-dependent pathways in neutrophil homeostasis.
This study also showed that different mechanisms mediate the enhanced IL-1 production by IKK-deficient macrophages and neutrophils. In IKK-deficient macrophages, the increase in IL-1 secretion was not due to increased pro-IL-1 mRNA induction but rather resulted from increased apoptosis and activation of caspase-1, which carries out the processing of pro-IL-1. More specifically, the authors showed that the protein product of the NF-B-dependent anti-apoptotic gene Pai2 (plasminogen activator inhibitor 2) negatively regulates caspase-1-dependent IL-1 release in macrophages. In IKK-deficient neutrophils, however, IKK deficiency attenuates apoptosis and instead an increased serine protease activity (particularly proteinase-3 and, to a lesser extent, neutrophil elastase activity) that results from defective NF-B activation accounts for the processing of pro-IL-1 and the release of IL-1.
In IKKmye and IKK mice, IKK deficiency is targeted only to certain cells, and therefore does not mimic a potential therapeutic intervention with an IKK inhibitor that would target all cells. So, the authors also used a pharmacological approach using a selective IKK inhibitor. They showed that the prolonged inhibition of IKK in this manner also enhanced pro-IL-1 processing and thereby led to increased endotoxin-induced shock and mortality.
These unanticipated findings have revealed a new negative regulatory mechanism for IKK-dependent NF-B activation that functions post-transcriptionally by inhibiting pro-IL-1 processing. More importantly, these results raise concerns about the use of IKK inhibitors as anti-inflammatory therapies.
Marta Tufet
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