JNK1 is protective for the progression of NEMO-dependent hepatitis

• Published in: Zeitschrift für Gastroenterologie
• Main Authors: Cubero, FJ, Zhao, G, Hatting, M, Drvarov, O, Nevzorova, Y, Al Massoudi, M, Gassler, N, Liedtke, C, Trautwein, C
• Format: Conference Proceeding
• Language: English
• Published: 09.01.2012
• Subjects: JNK1; JNK2; fibrosis; tumorigenesis; NEMO; TNF
• ISSN: 0044-2771; 1439-7803
• DOI: 10.1055/s-0031-1295735

Aims: Deletion of the regulatory subunit IKKγ/NEMO of NF-κB in hepatocytes (NEMO Δhepa ) triggers chronic inflammation and spontaneous hepatocellular carcinoma (HCC). We have previously reported that JNK in NEMO Δhepa mice is chronically activated which suggests that the JNK signaling pathway is essential in the progression of the disease. Aims: to elucidate the role of JNK1 and JNK2 in the development of hepatitis, steatosis, fibrosis and tumor development proliferation in a spontaneous model of liver injury. Methods : we generated Nemo Δhepa /JNK1 -/- and Nemo Δhepa /JNK2 -/- and their respective controls and characterized their phenotype during the progression of liver disease. Liver damage was measured by serum transaminases, histological, immunohistochemical and immunofluorescence, and biochemical and molecular biology techniques. Results : The deletion of JNK1 exacerbated the NEMO Δhepa phenotype elucidated by increased hepatitis, liver fibrosis, and tumor development. NEMO Δhepa /JNK1 -/- mice showed mitotic chaos, rupture of cytoskeleton and cell proliferation accompanied by a higher rate of apoptosis and strong infiltration of CD45 + cells, higher TNF expression, production of lipid peroxides. In turn, NEMO Δhepa /JNK2 -/- mutant mice did not show differences in the development of hepatitis, fibrosis and tumor development when compared to NEMO Δhepa . However, NEMO Δhepa /JNK2 -/- display glucose intolerance and increased liver deposition indicated increased steatosis and associated metabolic changes. Conclusion : In the NEMO Δhepa mice model of spontaneous liver injury, JNK1 and JNK2 exert distinct roles in the development of hepatitis, steatosis, liver fibrosis and HCC. While JNK1 partially protects from developing inflammation, fibrosis and tumor development, JNK2 decreases the progression of steatosis. Further development cell lineage–specific knockdown systems will provide more answers and extend the possibility of JNK genes targeting therapy.