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

Iris Lavon, Iris Goldberg, Sharon Amit, Limor Landsman, Steffen Jung, Ben Zion Tsuberi, Iris Barshack, Juri Kopolovic, Eitan Galun, Hermann Bujard, Yinon Ben-Neriah*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

147 Scopus citations

Abstract

Based on the essential involvement of NF-κB 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. Yet, given the essential function of NF-κB in the embryonic liver, it is important to determine its necessity in the liver beyond embryogenesis. NF- κB is normally retained in the cytoplasm by its inhibitor IκB, which is eliminated upon cell stimulation through phosphorylation-dependent ubiquitin degradation. Here, we directed a degradation-resistant IκBα transgene to mouse hepatocytes in an inducible manner and showed substantial tissue specificity using various means, including a new method for live-animal imaging. Transgene expression resulted in obstruction of NF-κB activation, yet produced no signs of liver dysfunction, even when implemented over 15 months. However, the transgene-expressing mice were very vulnerable both to a severe immune challenge and to a systemic bacterial infection. Despite having intact immunocytes and inflammatory cells, these mice were unable to clear Listeria monocytogenes from the liver and succumbed to sepsis. These findings indicate the essential function of the hepatocyte through NF-κB activation in certain systemic infections, possibly by coordinating innate immunity in the liver.

Original languageAmerican English
Pages (from-to)573-577
Number of pages5
JournalNature Medicine
Volume6
Issue number5
DOIs
StatePublished - May 2000

Bibliographical note

Funding Information:
Acknowledgments We thank E. Zeira for her help in the bioluminescence imaging; U. Bartenstein and A. Pinkhasov for help with the histopathology analysis; and A. Yaron, I. Alkalay and A. Mahler for comments on the manuscript. This research was supported by grants from the Israel Ministry of Science: Strategic Research in Biotechnology, the Israel Science Foundation funded by the Israel Academy for Sciences and Humanities-Centers of Excellence Program, the German-Israel Foundation for Scientific Research and Development, German-Israeli Program (DIP) and the Horvitz foundation.

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