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-kappaB 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-kappaB in the embryonic liver, it is important to determine its necessity in the liver beyond embryogenesis. NF-kappaB is normally retained in the cytoplasm by its inhibitor IkappaB, which is eliminated upon cell stimulation through phosphorylation-dependent ubiquitin degradation. Here, we directed a degradation-resistant IkappaBalpha 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-kappaB 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-kappaB activation in certain systemic infections, possibly by coordinating innate immunity in the liver.

Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis

“…14,32 Similarly, 2 independent laboratories confirmed that mice with hepatocyte-targeted deletion of ikk␤ (ikk␤ hep ) develop with normal liver structure and function and do not display elevated susceptibility to hepatocyte apoptosis induced by soluble TNF-␣ or lipopolysaccharide. 33,34 It is concluded that the canonical IKK␤ driven NF-B pathway is not essential for hepatocyte survival in the normal liver or upon challenge from physiological doses of endotoxin or TNF-␣.…”

“…For example, both ⌬N-I B␣ and ikk␤ hep livers were more susceptible to concanavalin-A-induced hepatocyte apoptosis. 32,33 This may reflect the ability of concanavalin-A to trigger activation of both TNFR1 (the receptor for soluble TNF-␣) and TNFR2 (the receptor for membrane bound TNF-␣), which results in robust and prolonged activation of proapoptotic Jun N-terminal kinase. 33 Because concanavalin-A provides a model for T cell-mediated hepatocyte death, it is possible that IKK␤-driven activation of NF-B functions as an important hepatocyte survival signal in alcoholic and viral liver disease.…”

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…Transgenic expression of degradation-resistant IkBa and IkBb isoforms Degradation-resistant IkBa and IkBb mutants (IkBm) that function as dominant inhibitors of NF-kB activation when expressed under the control of tissue-specific or developmentally restricted promoters have been used to probe NF-kB function in a range of cell types in mice, including B (Bendall et al, 1999) and T lymphocytes (Boothby et al, 1997;Esslinger et al, 1997;Attar et al, 1998;Ferreira et al, 1999;Hettmann et al, 1999;Voll et al, 2000;Hettmann and Leiden, 2000), muscle (Cai et al, 2004), neurons (Fridmacher et al, 2003), hepatocytes (Lavon et al, 2000;Cai et al, 2005), heart (Dawn et al, 2001), pancreas (Norlin et al, 2005) and skin (Seitz et al, 1998;van Hogerlinden et al, 1999). Although this approach has been highly successful, IkBm expression targeted to a particular tissue has been documented to generate distinct phenotypes, or a phenotype of varying severity in different transgenic founder lines.…”

Conditional and specific NF-κB blockade protects pancreatic beta cells from diabetogenic agents

“…The ToI-␤ mouse model was generated by cross-breeding two transgenic lines of mice: one carrying the inversely positioned ⌬NI B␣ (with the N-terminal deleted) and luciferase genes (⌬NI B␣-Luc), regulated by a bidirectional tetracycline-responsive element against a C57B͞6 ϫ BALB͞c background (44) and the second expressing the reverse tetracycline transactivator (rtTA) under the control of the rat insulin II promoter, consisting of the 9.5-kb 5Ј flanking region of the gene (RIP7-rtTA) against the C3H ϫ BALB͞c background (45). Transmission of both transgenes was monitored by PCR analysis from tail DNA by using the appropriate primers.…”