Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury
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 correla...
| Autores: | , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | Universidad Complutense de Madrid (UCM) |
| Repositorio: | Docta Complutense |
| Idioma: | inglés |
| OAI Identifier: | oai:docta.ucm.es:20.500.14352/97631 |
| Acceso en línea: | https://hdl.handle.net/20.500.14352/97631 |
| Access Level: | acceso abierto |
| Palabra clave: | 577 APAP Gene Regulation Mouse Model Pharmacologic Treatment Ciencias Biomédicas Biología Biología celular (Biología) Biología molecular (Biología) Medicina Gastroenterología y hepatología Inmunología 24 Ciencias de la Vida 2407 Biología Celular 2410 Biología Humana 2412 Inmunología 2415 Biología Molecular |
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Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver InjuryCubero Palero, Francisco JavierTrautwein, Christian577APAPGene RegulationMouse ModelPharmacologic TreatmentCiencias BiomédicasBiologíaBiología celular (Biología)Biología molecular (Biología)MedicinaGastroenterología y hepatologíaInmunología24 Ciencias de la Vida2407 Biología Celular2410 Biología Humana2412 Inmunología2415 Biología MolecularBACKGROUND & 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 antiinflammatory 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 (Jnk1Dhepa) or combination of Jnk1 and Jnk2 (JnkDhepa), 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 JnkDhepa mice produced a greater level of liver injury than that observed in Jnk1Dhepa 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 JnkDhepa mice, based on increased inflammation, cell proliferation, and fibrosis progression, compared with Jnk1Dhepa or control mice. Hepatocytes from JnkDhepa 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 JnkDhepa 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.ElsevierUniversidad Complutense de Madrid20162016-08-0220162016-08-02journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/97631reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/976312026-06-02T12:44:21Z |
| dc.title.none.fl_str_mv |
Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury |
| title |
Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury |
| spellingShingle |
Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury Cubero Palero, Francisco Javier 577 APAP Gene Regulation Mouse Model Pharmacologic Treatment Ciencias Biomédicas Biología Biología celular (Biología) Biología molecular (Biología) Medicina Gastroenterología y hepatología Inmunología 24 Ciencias de la Vida 2407 Biología Celular 2410 Biología Humana 2412 Inmunología 2415 Biología Molecular |
| title_short |
Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury |
| title_full |
Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury |
| title_fullStr |
Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury |
| title_full_unstemmed |
Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury |
| title_sort |
Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury |
| dc.creator.none.fl_str_mv |
Cubero Palero, Francisco Javier Trautwein, Christian |
| author |
Cubero Palero, Francisco Javier |
| author_facet |
Cubero Palero, Francisco Javier Trautwein, Christian |
| author_role |
author |
| author2 |
Trautwein, Christian |
| author2_role |
author |
| dc.contributor.none.fl_str_mv |
Universidad Complutense de Madrid |
| dc.subject.none.fl_str_mv |
577 APAP Gene Regulation Mouse Model Pharmacologic Treatment Ciencias Biomédicas Biología Biología celular (Biología) Biología molecular (Biología) Medicina Gastroenterología y hepatología Inmunología 24 Ciencias de la Vida 2407 Biología Celular 2410 Biología Humana 2412 Inmunología 2415 Biología Molecular |
| topic |
577 APAP Gene Regulation Mouse Model Pharmacologic Treatment Ciencias Biomédicas Biología Biología celular (Biología) Biología molecular (Biología) Medicina Gastroenterología y hepatología Inmunología 24 Ciencias de la Vida 2407 Biología Celular 2410 Biología Humana 2412 Inmunología 2415 Biología Molecular |
| description |
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 antiinflammatory 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 (Jnk1Dhepa) or combination of Jnk1 and Jnk2 (JnkDhepa), 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 JnkDhepa mice produced a greater level of liver injury than that observed in Jnk1Dhepa 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 JnkDhepa mice, based on increased inflammation, cell proliferation, and fibrosis progression, compared with Jnk1Dhepa or control mice. Hepatocytes from JnkDhepa 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 JnkDhepa 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. |
| publishDate |
2016 |
| dc.date.none.fl_str_mv |
2016 2016-08-02 2016 2016-08-02 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/20.500.14352/97631 |
| url |
https://hdl.handle.net/20.500.14352/97631 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
| publisher.none.fl_str_mv |
Elsevier |
| dc.source.none.fl_str_mv |
reponame:Docta Complutense instname:Universidad Complutense de Madrid (UCM) |
| instname_str |
Universidad Complutense de Madrid (UCM) |
| reponame_str |
Docta Complutense |
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Docta Complutense |
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|
| repository.mail.fl_str_mv |
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1869410131541753856 |
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15,301603 |