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Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury.
Gastroenterology. 2016 Apr; 150(4):968-81.G

Abstract

BACKGROUND & AIMS

c-Jun N-terminal kinase (JNK) 1 and JNK2 are expressed in hepatocytes and have overlapping and distinct functions. JNK proteins are activated via phosphorylation in response to acetaminophen- or carbon tetrachloride (CCl4)-induced liver damage; the level of activation correlates with the degree of injury. SP600125, a JNK inhibitor, has been reported to block acetaminophen-induced liver injury. We investigated the role of JNK in drug-induced liver injury (DILI) in liver tissue from patients and in mice with genetic deletion of JNK in hepatocytes.

METHODS

We studied liver sections from patients with DILI (due to acetaminophen, phenprocoumon, nonsteroidal anti-inflammatory drugs, or autoimmune hepatitis) or patients without acute liver failure (controls) collected from a DILI Biobank in Germany. Levels of total and activated (phosphorylated) JNK were measured by immunohistochemistry and Western blotting. Mice with hepatocyte-specific deletion of Jnk1 (Jnk1(Δhepa)) or combination of Jnk1 and Jnk2 (Jnk(Δhepa)), as well as Jnk1-floxed C57BL/6 (control) mice, were given injections of CCl4 (to induce fibrosis) or acetaminophen (to induce toxic liver injury). We performed gene expression microarray and phosphoproteomic analyses to determine mechanisms of JNK activity in hepatocytes.

RESULTS

Liver samples from DILI patients contained more activated JNK, predominantly in nuclei of hepatocytes and in immune cells, than healthy tissue. Administration of acetaminophen to Jnk(Δhepa) mice produced a greater level of liver injury than that observed in Jnk1(Δhepa) or control mice, based on levels of serum markers and microscopic and histologic analysis of liver tissues. Administration of CCl4 also induced stronger hepatic injury in Jnk(Δhepa) mice, based on increased inflammation, cell proliferation, and fibrosis progression, compared with Jnk1(Δhepa) or control mice. Hepatocytes from Jnk(Δhepa) mice given acetaminophen had an increased oxidative stress response, leading to decreased activation of adenosine monophosphate-activated protein kinase, total protein adenosine monophosphate-activated protein kinase levels, and pJunD and subsequent necrosis. Administration of SP600125 before or with acetaminophen protected Jnk(Δhepa) and control mice from liver injury.

CONCLUSIONS

In hepatocytes, JNK1 and JNK2 appear to have combined effects in protecting mice from CCl4- and acetaminophen-induced liver injury. It is important to study the tissue-specific functions of both proteins, rather than just JNK1, in the onset of toxic liver injury. JNK inhibition with SP600125 shows off-target effects.

Authors+Show Affiliations

Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany. Electronic address: fcubero@ukaachen.de.Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.Department of Gastroenterology and Hepatology, University Hospital Duisburg-Essen, Essen, Germany.Nutrition, Metabolism & Genomics group, Wageningen University, Division of Human Nutrition, Wageningen, The Netherlands.Norwich Medical School, University of East Anglia, Norwich, United Kingdom.Proteomics Facility, University Hospital, RWTH Aachen, Germany.Institute of Pathology, University Hospital, RWTH Aachen, Germany.Department of Gastroenterology and Hepatology, University Hospital Duisburg-Essen, Essen, Germany.Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.Howard Hughes Medical Institute and University of Massachusetts Medical School, Worcester, Massachusetts.Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany. Electronic address: ctrautwein@ukaachen.de.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26708719

Citation

Cubero, Francisco Javier, et al. "Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury." Gastroenterology, vol. 150, no. 4, 2016, pp. 968-81.
Cubero FJ, Zoubek ME, Hu W, et al. Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury. Gastroenterology. 2016;150(4):968-81.
Cubero, F. J., Zoubek, M. E., Hu, W., Peng, J., Zhao, G., Nevzorova, Y. A., Al Masaoudi, M., Bechmann, L. P., Boekschoten, M. V., Muller, M., Preisinger, C., Gassler, N., Canbay, A. E., Luedde, T., Davis, R. J., Liedtke, C., & Trautwein, C. (2016). Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury. Gastroenterology, 150(4), 968-81. https://doi.org/10.1053/j.gastro.2015.12.019
Cubero FJ, et al. Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury. Gastroenterology. 2016;150(4):968-81. PubMed PMID: 26708719.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury. AU - Cubero,Francisco Javier, AU - Zoubek,Miguel Eugenio, AU - Hu,Wei, AU - Peng,Jin, AU - Zhao,Gang, AU - Nevzorova,Yulia A, AU - Al Masaoudi,Malika, AU - Bechmann,Lars P, AU - Boekschoten,Mark V, AU - Muller,Michael, AU - Preisinger,Christian, AU - Gassler,Nikolaus, AU - Canbay,Ali E, AU - Luedde,Tom, AU - Davis,Roger J, AU - Liedtke,Christian, AU - Trautwein,Christian, Y1 - 2015/12/19/ PY - 2014/09/15/received PY - 2015/11/16/revised PY - 2015/12/12/accepted PY - 2015/12/29/entrez PY - 2015/12/29/pubmed PY - 2016/8/9/medline KW - APAP KW - Gene Regulation KW - Mouse Model KW - Pharmacologic Treatment SP - 968 EP - 81 JF - Gastroenterology JO - Gastroenterology VL - 150 IS - 4 N2 - BACKGROUND & AIMS: c-Jun N-terminal kinase (JNK) 1 and JNK2 are expressed in hepatocytes and have overlapping and distinct functions. JNK proteins are activated via phosphorylation in response to acetaminophen- or carbon tetrachloride (CCl4)-induced liver damage; the level of activation correlates with the degree of injury. SP600125, a JNK inhibitor, has been reported to block acetaminophen-induced liver injury. We investigated the role of JNK in drug-induced liver injury (DILI) in liver tissue from patients and in mice with genetic deletion of JNK in hepatocytes. METHODS: We studied liver sections from patients with DILI (due to acetaminophen, phenprocoumon, nonsteroidal anti-inflammatory drugs, or autoimmune hepatitis) or patients without acute liver failure (controls) collected from a DILI Biobank in Germany. Levels of total and activated (phosphorylated) JNK were measured by immunohistochemistry and Western blotting. Mice with hepatocyte-specific deletion of Jnk1 (Jnk1(Δhepa)) or combination of Jnk1 and Jnk2 (Jnk(Δhepa)), as well as Jnk1-floxed C57BL/6 (control) mice, were given injections of CCl4 (to induce fibrosis) or acetaminophen (to induce toxic liver injury). We performed gene expression microarray and phosphoproteomic analyses to determine mechanisms of JNK activity in hepatocytes. RESULTS: Liver samples from DILI patients contained more activated JNK, predominantly in nuclei of hepatocytes and in immune cells, than healthy tissue. Administration of acetaminophen to Jnk(Δhepa) mice produced a greater level of liver injury than that observed in Jnk1(Δhepa) or control mice, based on levels of serum markers and microscopic and histologic analysis of liver tissues. Administration of CCl4 also induced stronger hepatic injury in Jnk(Δhepa) mice, based on increased inflammation, cell proliferation, and fibrosis progression, compared with Jnk1(Δhepa) or control mice. Hepatocytes from Jnk(Δhepa) mice given acetaminophen had an increased oxidative stress response, leading to decreased activation of adenosine monophosphate-activated protein kinase, total protein adenosine monophosphate-activated protein kinase levels, and pJunD and subsequent necrosis. Administration of SP600125 before or with acetaminophen protected Jnk(Δhepa) and control mice from liver injury. CONCLUSIONS: In hepatocytes, JNK1 and JNK2 appear to have combined effects in protecting mice from CCl4- and acetaminophen-induced liver injury. It is important to study the tissue-specific functions of both proteins, rather than just JNK1, in the onset of toxic liver injury. JNK inhibition with SP600125 shows off-target effects. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/26708719/Combined_Activities_of_JNK1_and_JNK2_in_Hepatocytes_Protect_Against_Toxic_Liver_Injury_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(15)01814-4 DB - PRIME DP - Unbound Medicine ER -