Hematopoietic cells-derived Jnk1 is crucial for chronic inflammation and carcinogenesis in an experimental model of liver injury

  • Francisco J. Cubero (Creator)
  • Gang Zhao (Creator)
  • Yulia A. Nevzorova (Creator)
  • Maximilian Hatting (Creator)
  • Malika Al Masaoudi (Creator)
  • Julien Verdier (Creator)
  • Jin Peng (Creator)
  • Frederik M. Schaefer (Creator)
  • Nadine Hermanns (Creator)
  • Mark Boekschoten (Creator)
  • Christoph Grouls (Creator)
  • Nikolaus Gassler (Creator)
  • Fabian Kiessling (Creator)
  • Michael Muller (Creator)
  • Roger J. Davis (Creator)
  • Christian Liedtke (Creator)
  • Christian Trautwein (Creator)

Dataset

Description

Chronic liver injury triggers complications such as liver fibrosis and hepatocellular carcinoma (HCC), which are associated with alterations in distinct signaling pathways. Of particular interest is the interaction between mechanisms controlled by IKKγ/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 (NEMOΔhepa), a genetic model of chronic inflammatory liver injury. We generated global Jnk1-/-/NEMOΔhepa and Jnk2-/-/NEMOΔhepa mice by crossing NEMOΔhepa mice with Jnk1-/- and Jnk2-/- 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 analyzed the expression of NEMO and pJnk in human diseased-livers. Deletion of Jnk1 significantly aggravated the progression of liver disease, exacerbating apoptosis, compensatory proliferation and carcinogenesis in NEMOΔhepa mice. Jnk2-/-/NEMOΔhepa showed increased RIP-1 and RIP-3 expression and hepatic inflammation. Jnk1 in hematopoietic cells rather than hepatocytes had an impact on the progression of chronic liver disease in NEMOΔhepa livers. These findings are of clinical relevance since NEMO expression was down-regulated in hepatocytes of patients with HCC whereas NEMO and pJnk were expressed in a large amount of infiltrating cells. While Jnk1 is protective in NEMOΔhepa-depleted hepatocytes, Jnk1 in hematopoietic cells rather than hepatocytes is a crucial driver of hepatic injury. These results elucidate the complex function of Jnk in chronic inflammatory liver disease.
Date made available22 Jun 2015
PublisherWageningen University

Research Output

Haematopoietic cell-derived Jnk1 is crucial for chronic inflammation and carcinogenesis in an experimental model of liver injury

Cubero, F. J., Zhao, G., Nevzorova, Y. A., Hatting, M., Al Masaoudi, M., Verdier, J., Peng, J., Schaefer, F. M., Hermanns, N., Boekschoten, M. V., Grouls, C., Gassler, N., Kiessling, F., Muller, M. R., Davis, R. J., Liedtke, C. & Trautwein, C., 2015, In : Journal of Hepatology. 62, 1, p. 140-149

Research output: Contribution to journalArticleAcademicpeer-review

  • 12 Citations (Scopus)

    Cite this

    Cubero, F. J. (Creator), Zhao, G. (Creator), Nevzorova, Y. A. (Creator), Hatting, M. (Creator), Al Masaoudi, M. (Creator), Verdier, J. (Creator), Peng, J. (Creator), Schaefer, F. M. (Creator), Hermanns, N. (Creator), Boekschoten, M. (Creator), Grouls, C. (Creator), Gassler, N. (Creator), Kiessling, F. (Creator), Muller, M. (Creator), Davis, R. J. (Creator), Liedtke, C. (Creator), Trautwein, C. (Creator) (22 Jun 2015). Hematopoietic cells-derived Jnk1 is crucial for chronic inflammation and carcinogenesis in an experimental model of liver injury. Wageningen University.