Z Gastroenterol 2019; 57(01): e19-e20
DOI: 10.1055/s-0038-1677091
1. Basic Hepatology (Fibrogenesis, NPC, Transport)
Georg Thieme Verlag KG Stuttgart · New York

Combined function of c-Jun N-terminal kinases in hepatocytes protects mice from fibrosis development during cholestatic liver injury

MR Mohamed
1   Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany
2   Therapeutic Chemistry Department, National Research Centre (NRC), Dokki, Cairo, Egypt
,
FJ Cubero
1   Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany
3   Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid, Spain
4   12 de Octubre Health Research Institute (imas12), Madrid, Spain
,
G Zhao
1   Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany
,
YA Nevzorova
1   Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany
4   12 de Octubre Health Research Institute (imas12), Madrid, Spain
5   Department of Physiology, Genetics and Microbiology, Faculty of Biology, Complutense University, Madrid, Spain
,
N Gassler
6   Institute of Pathology, University Hospital, Braunschweig, Germany
,
RJ Davis
7   Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, USA
,
C Trautwein
1   Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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Background:

Cholestatic liver injury (CLI) is one of the major causative factors for liver fibrosis. CLI triggers c-Jun N-terminal kinases (JNK) activation. Interestingly, we have previously shown that the JNK1 is responsible for hepatic stellate cells (HSCs) activation in liver fibrosis. However as different cell types are involved in determining the relevance of JNK1 and/or 2 during fibrogenesis, we aimed here to specifically define the cell type specific role of JNKs during CLI for fibrosis.

Methods:

Jnkf/f wildtype (WT), Jnk2–/– and JNKΔhepa (hepatocyte-specific JNK1 and constitutive JNK2 deletion/complete deletion of JNK1 and 2 in hepatocytes) mice were subjected to bile duct ligation (BDL)-induced liver fibrosis. In addition, immunoblotting, immunofluorescence and immunohistochemical studies were performed. Furthermore, bone marrow transplantation experiments were incorporated.

Results:

Serum markers of liver damage – liver transaminases- and liver histology revealed increased cell injury and compensatory proliferation in mice with combined deletion of JNK1 and JNK2 in hepatocytes compared to Jnk2-/- and WT mice. TUNEL staining and cleaved caspase 3 staining demonstrated that this effect is directly mediated by a higher rate of hepatocyte apoptosis. Consequently, BDL caused increased markers of liver fibrosis in JNKΔhepa livers including Sirius red staining as well as Collagen IA1, TIMP1 and MMP2 in WT mice. However, no differences were found in Jnk2–/– compared to JNKΔhepa livers. Concomitantly, infiltration of immune cells and inflammatory cytokines measured by CD11b, F4/80, TNF, TGF β, IL-6, IL-1α/β were strongly up-regulated in WT mice but no difference was evident between Jnk2–/– and JNKΔhepa BDL-treated livers. Moreover, BDL treated chimeric JNKΔhepa mice reconstituted either with WT (WT to JNKΔhepa) or JNKΔhepa BM (JNKΔhepa to JNKΔhepa) revealed significantly higher liver damage and liver fibrogenesis after BDL than WT mice reconstituted with either with WT BM (WT to WT) or JNKΔhepa BM (JNKΔhepa to WT)

Conclusion:

Combined JNK function is protective in hepatocytes during cholestatic liver injury. This JNK-dependent effect is directly mediated by inhibiting caspase8-dependent apoptosis during CLI.