Haematopoietic cell-derived Jnk1 is crucial for chronic inflammation and carcinogenesis in an experimental model of liver injury
Program in Molecular Medicine
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
BACKGROUND and AIMS: Chronic liver injury triggers complications such as liver fibrosis and hepatocellular carcinoma (HCC), which are associated with alterations in distinct signalling pathways. Of particular interest is the interaction between mechanisms controlled by IKKgamma/NEMO, the regulatory IKK subunit, and Jnk activation for directing cell death and survival. In the present study, we aimed to define the relevance of Jnk in hepatocyte-specific NEMO knockout mice (NEMO(Deltahepa)), a genetic model of chronic inflammatory liver injury.
METHODS: We generated Jnk1(-/-)/NEMO(Deltahepa) and Jnk2(-/-)/NEMO(Deltahepa) mice by crossing NEMO(Deltahepa) mice with Jnk1 and Jnk2 global deficient animals, respectively, and examined the progression of chronic liver disease. Moreover, we investigated the expression of Jnk during acute liver injury, evaluated the role of Jnk1 in bone marrow-derived cells, and analysed the expression of NEMO and p-JNK in human diseased-livers.
RESULTS: Deletion of Jnk1 significantly aggravated the progression of liver disease, exacerbating apoptosis, compensatory proliferation and carcinogenesis in NEMO(Deltahepa) mice. Conversely, Jnk2(-/-)/NEMO(Deltahepa) displayed hepatic inflammation. By using bone marrow transfer, we observed that Jnk1 in haematopoietic cells had an impact on the progression of chronic liver disease in NEMO(Deltahepa) livers. These findings are of clinical relevance since NEMO expression was downregulated in hepatocytes of patients with HCC whereas NEMO and p-JNK were expressed in a large amount of infiltrating cells.
CONCLUSIONS: A synergistic function of Jnk1 in haematopoietic cells and hepatocytes might be relevant for the development of chronic liver injury. These results elucidate the complex function of Jnk in chronic inflammatory liver disease.
Apoptosis, HCC, IKKγ/NEMO, Jnk1, Jnk2, Necrosis
DOI of Published Version
J Hepatol. 2015 Jan;62(1):140-9. doi: 10.1016/j.jhep.2014.08.029. Epub 2014 Aug 27. Link to article on publisher's site
Journal of hepatology
Cubero, Francisco Javier; Zhao, Gang; Nevzorova, Yulia A.; Hatting, Maximilian; Al Masaoudi, Malika; Verdier, Julien; Peng, Jin; Schaefer, Frederik M.; Hermanns, Nadine; Boekschoten, Mark V.; Grouls, Christoph; Gassler, Nikolaus; Kiessling, Fabian; Muller, Michael; Davis, Roger J.; Liedtke, Christian; and Trautwein, Christian, "Haematopoietic cell-derived Jnk1 is crucial for chronic inflammation and carcinogenesis in an experimental model of liver injury" (2015). Davis Lab Publications. 12.