High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-kappa B activation

Based on the essential involvement of NF-kappa B in immune and inflammatory responses and its apoptosis-rescue function in normal and malignant cells, inhibitors of this transcription factor are potential therapeutics for the treatment of a wide range of diseases, from bronchial asthma to cancer(1,2 ). Yet, given the essential function of NF-kappa B in the embryonic liver(3 -6), it is important to determine its necessity in the liver beyond embryog enesis. NF-kappa B is normally retained in the cytoplasm by its inhibitor I kappa B, which is eliminated upon cell stimulation through phosphorylation -dependent ubiquitin degradation(7). Here, we directed a degradation-resist ant I kappa B alpha transgene to mouse hepatocytes in an inducible manner a nd showed substantial tissue specificity using various means, including a n ew method for live-animal imaging. Transgene expression resulted in obstruc tion of NF-kappa B activation, yet produced no signs of liver dysfunction, even when implemented over 15 months. However, the transgene-expressing mic e were very vulnerable both to a severe immune challenge and to a systemic bacterial infection. Despite having intact immunocytes and inflammatory cel ls, these mice were unable to clear Listeria monocytogenes from the liver a nd succumbed to sepsis. These findings indicate the essential function of t he hepatocyte through NF-kappa B activation in certain systemic infections, possibly by coordinating innate immunity in the liver.