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

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 cancer1,2. Yet, given the essential function of NF-κB in the embryonic liver3,4,5,6, 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 degradation7. 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.

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Figure 1: Conditional expression of a mutant IκBα transgene in mouse liver.
Figure 2: Hepatocyte-specific transgene expression results in inhibition of NF-κB and in profound liver damage induced by concavalin A.
Figure 3: Sequela of Listeria monocytogenes infection in transgenic and wild-type mice.
Figure 4: Function of hepatocyte NF-kB in clearing a bacterial infection from the liver.

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References

  1. Barnes, P.J. & Karin, M. Nuclear factor-κB—A pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071 (1997).

    Article  CAS  Google Scholar 

  2. Wang, C.Y., Cusack, J.C., Jr., Liu, R. & Baldwin, A.S., Jr., Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-κB. Nature Med. 5, 412–417 (1999).

    Article  Google Scholar 

  3. Beg, A.A., Sha, W.C., Bronson, R.T., Ghosh, S. & Baltimore, D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 376, 167–169 (1995).

    Article  CAS  Google Scholar 

  4. Li, Z.-W. et al. The IKKβ subunit of IκB kinase (IKK) is essential for NF-κB activation and prevention of apoptosis. J. Exp. Med. 189, 1–7 (1999).

    Article  Google Scholar 

  5. Li, Q., Van Antwerp, D., Mercurio, F., Lee, K.-F. & Verma, I.M. Severe liver degeneration in mice lacking the IκB kinase 2 gene. Science 284, 321–325 (1999).

    Article  CAS  Google Scholar 

  6. Tanaka, M. et al. Embryonic lethality, liver degeneration, and impaired NF-κB activation in IKK-—deficient mice. Immunity 10, 421–429 (1999).

    Article  CAS  Google Scholar 

  7. Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Ann. Rev. Immunol. 18, 621–663 (2000).

    Article  CAS  Google Scholar 

  8. Kistner, A. et al. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc. Natl. Acad. Sci. USA 93, 10933–10938 (1996).

    Article  CAS  Google Scholar 

  9. Attar, R.M. et al. Genetic approaches to study Rel/NFκB/I κB function in mice. Semin. Cancer Biol. 8, 93–101 (1997).

    Article  CAS  Google Scholar 

  10. Brown, K., Gerstberger, S., Carlson, L., Franzoso, G. & Siebenlist, U. Control of IκBα proteolysis by site-specific, signal-induced phosphorylation. Science 267, 1485–1491 (1995).

    Article  CAS  Google Scholar 

  11. Bellas, R.E., FitzGerald, M.J., Fausto, N. & Sonenshein, G.E. Inhibition of NF-κB activity induces apoptosis in murine hepatocytes. Am. J. Pathol. 151, 891–896 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Iimuro, Y. et al. NFκB prevents apoptosis and liver dysfunction during liver regeneration. J. Clin. Invest. 101, 802–811 (1998).

    Article  CAS  Google Scholar 

  13. Bradham, C.A., Plumpe, J., Manns, M.P., Brenner, D.A. & Trautwein, C. Mechanisms of hepatic toxicity. I. TNF-induced liver injury. Am. J. Physiol. 275, G387–92 (1998).

    CAS  PubMed  Google Scholar 

  14. Taub, R. Blocking NF-κB in the liver: the good and bad news. Hepatology 27, 1445–1446 (1998).

    Article  CAS  Google Scholar 

  15. Contag, C.H. et al. Visualizing gene expression in living mammals using a bioluminescent reporter. Photochem. Photobiol. 66, 523–531 (1997).

    Article  CAS  Google Scholar 

  16. Tiegs, G., Hentschel, J. & Wendel, A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J. Clin. Invest. 90, 196–203 (1992).

    Article  CAS  Google Scholar 

  17. Mizuhara, H. et al. T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6. J. Exp. Med. 179, 1529–1537 (1994).

    Article  CAS  Google Scholar 

  18. Kaufmann, S.H. Immunity to intracellular bacteria. Annu. Rev. Immunol. 11, 129–163 (1993).

    Article  CAS  Google Scholar 

  19. Armstrong, D. in Principles and Practice of Infectious Diseases (eds. Mandell, G.L., Bennett, J.E. & Dolin R.) 1880–1885 (Churchill Livingstone, New York, 1995).

    Google Scholar 

  20. Pfeffer, K. et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73, 457–467 (1993).

    Article  CAS  Google Scholar 

  21. Endres, R. et al. Listeriosis in p47(phox−/−) and TRp55−/− mice: protection despite absence of ROI and susceptibility despite presence of RNI. Immunity 7, 419–432 (1997).

    Article  CAS  Google Scholar 

  22. Rogers, H.W., Callery, M.P., Deck, B. & Unanue, E.R. Listeria monocytogenes induces apoptosis of infected hepatocytes. J. Immunol. 156, 679–684 (1996).

    CAS  PubMed  Google Scholar 

  23. Conlan, J.W. & North, R.J. Neutrophils are essential for early anti-Listeria defense in the liver, but not in the spleen or peritoneal cavity, as revealed by a granulocyte-depleting monoclonal antibody. J. Exp. Med. 179, 259–268 (1994).

    Article  CAS  Google Scholar 

  24. Talbot, D., Descombes, P. & Schibler, U. The 5′ flanking region of the rat LAP (C/EBP β) gene can direct high-level, position-independent, copy number-dependent expression in multiple tissues in transgenic mice. Nucleic Acids Res 22, 756–766 (1994).

    Article  CAS  Google Scholar 

  25. Gossen, M. et al. Transcriptional activation by tetracyclines in mammalian cells. Science 268, 1766–1769 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

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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Correspondence to Yinon Ben-Neriah.

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Lavon, I., Goldberg, I., Amit, S. et al. High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-κB activation. Nat Med 6, 573–577 (2000). https://doi.org/10.1038/75057

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