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Nuclear factor kappa B (NF-κB) is a highly conserved transcriptional regulator which has evolved to allow the cells to respond to stressful conditions and to devise appropriate defensive strategies.1 Two lines of protection are pivotally coordinated by members of this family, specifically inflammation, including antimicrobial resistance, and inhibition of apoptotic cell death. Although NF-κB is certainly important in many tissues, it has a particular relevance in liver pathophysiology, as indicated by the fact that interference with the “canonical” NF-κB pathway by gene deletion leads to death in utero due to massive hepatocyte apoptosis.2 Because NF-κB is a regulator of both inflammation and hepatocyte survival, the relevance of cellular specificity of hepatic NF-κB activation can be easily anticipated by the fact that the liver possesses the highest number of macrophages compared to any other tissues, and that macrophages decisively contribute to many inflammatory processes. On the other hand, hepatocytes are critically dependent on the integrity of the NF-κB pathway to survive in adverse conditions, such as those that accompany severe inflammation. For these reasons, strategies that could efficiently block NF-κB activation in a cell-specific fashion are extremely appealing, in order to inhibit inflammation while preserving hepatocyte survival.
The study of Hoffmann et al3 published in this issue of Gut (see page 1670) addresses this important issue, describing the effects of a strategy directed to selectively inhibit NF-κB in Kupffer cells, in different murine models of liver injury. Unlike previous studies, where cell-specific inhibition of NF-κB was obtained generating conditional knock-out mice, the strategy utilised by Hoffmann et al3 …
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