Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition.

Johannes Kluwe; Jean-Philippe Pradere; Geum-Youn Gwak; Ali Mencin; De Minicis Samuele; Christoph H Osterreicher; Jordi Colmenero; Ramon Bataller; Robert F Schwabe

Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition.

Standard

Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. / Kluwe, Johannes; Pradere, Jean-Philippe; Gwak, Geum-Youn; Mencin, Ali; Samuele, De Minicis; Osterreicher, Christoph H; Colmenero, Jordi; Bataller, Ramon; Schwabe, Robert F.

in: GASTROENTEROLOGY, Jahrgang 138, Nr. 1, 1, 2010, S. 347-359.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Kluwe, J, Pradere, J-P, Gwak, G-Y, Mencin, A, Samuele, DM, Osterreicher, CH, Colmenero, J, Bataller, R & Schwabe, RF 2010, 'Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition.', GASTROENTEROLOGY, Jg. 138, Nr. 1, 1, S. 347-359. <http://www.ncbi.nlm.nih.gov/pubmed/19782079?dopt=Citation>

APA

Kluwe, J., Pradere, J-P., Gwak, G-Y., Mencin, A., Samuele, D. M., Osterreicher, C. H., Colmenero, J., Bataller, R., & Schwabe, R. F. (2010). Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. GASTROENTEROLOGY, 138(1), 347-359. [1]. http://www.ncbi.nlm.nih.gov/pubmed/19782079?dopt=Citation

Vancouver

Kluwe J, Pradere J-P, Gwak G-Y, Mencin A, Samuele DM, Osterreicher CH et al. Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. GASTROENTEROLOGY. 2010;138(1):347-359. 1.

Bibtex

@article{48b9d3fb7ac04ec7b1912f7f8a540ef9,

title = "Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition.",

abstract = "BACKGROUND ; AIMS: c-Jun N-terminal kinase (JNK) is activated by multiple profibrogenic mediators; JNK activation occurs during toxic, metabolic, and autoimmune liver injury. However, its role in hepatic fibrogenesis is unknown. METHODS: JNK phosphorylation was detected by immunoblot analysis and confocal immunofluorescent microscopy in fibrotic livers from mice after bile duct ligation (BDL) or CCl(4) administration and in liver samples from patients with chronic hepatitis C and non-alcoholic steatohepatitis. Fibrogenesis was investigated in mice given the JNK inhibitor SP600125 and in JNK1- and JNK2-deficient mice following BDL or CCl(4) administration. Hepatic stellate cell (HSC) activation was determined in primary mouse HSCs incubated with pan-JNK inhibitors SP600125 and VIII. RESULTS: JNK phosphorylation was strongly increased in livers of mice following BDL or CCl(4) administration as well as in human fibrotic livers, occurring predominantly in myofibroblasts. In vitro, pan-JNK inhibitors prevented transforming growth factor (TGF) beta-, platelet-derived growth factor-, and angiotensin II-induced murine HSC activation and decreased platelet-derived growth factor and TGF-beta signaling in human HSCs. In vivo, pan-JNK inhibition did not affect liver injury but significantly reduced fibrosis after BDL or CCl(4). JNK1-deficient mice had decreased fibrosis after BDL or CCl(4), whereas JNK2-deficient mice displayed increased fibrosis after BDL but fibrosis was not changed after CCl(4). Moreover, patients with chronic hepatitis C who displayed decreased fibrosis in response to the angiotensin receptor type 1 blocker losartan showed decreased JNK phosphorylation. CONCLUSIONS: JNK is involved in HSC activation and fibrogenesis and represents a potential target for antifibrotic treatment approaches.",

keywords = "Animals, Humans, Angiotensin II pharmacology, Anthracenes pharmacology, Carrier Proteins antagonists, inhibitors, Cell Division drug effects, Cells, Cultured, Disease Models, Animal, Fatty Liver drug therapy, Fibroblasts enzymology, Hepatic Stellate Cells enzymology, Hepatitis C, Chronic drug therapy, Liver Cirrhosis drug therapy, Membrane Glycoproteins antagonists, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Mutant Strains, Mitogen-Activated Protein Kinase 9 metabolism, Phosphorylation physiology, Platelet-Derived Growth Factor pharmacology, Protein Kinase Inhibitors pharmacology, Transforming Growth Factor beta pharmacology, Animals, Humans, Angiotensin II pharmacology, Anthracenes pharmacology, Carrier Proteins antagonists, inhibitors, Cell Division drug effects, Cells, Cultured, Disease Models, Animal, Fatty Liver drug therapy, Fibroblasts enzymology, Hepatic Stellate Cells enzymology, Hepatitis C, Chronic drug therapy, Liver Cirrhosis drug therapy, Membrane Glycoproteins antagonists, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Mutant Strains, Mitogen-Activated Protein Kinase 9 metabolism, Phosphorylation physiology, Platelet-Derived Growth Factor pharmacology, Protein Kinase Inhibitors pharmacology, Transforming Growth Factor beta pharmacology",

author = "Johannes Kluwe and Jean-Philippe Pradere and Geum-Youn Gwak and Ali Mencin and Samuele, {De Minicis} and Osterreicher, {Christoph H} and Jordi Colmenero and Ramon Bataller and Schwabe, {Robert F}",

year = "2010",

language = "Deutsch",

volume = "138",

pages = "347--359",

journal = "GASTROENTEROLOGY",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "1",

}

RIS

TY - JOUR

T1 - Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition.

AU - Kluwe, Johannes

AU - Pradere, Jean-Philippe

AU - Gwak, Geum-Youn

AU - Mencin, Ali

AU - Samuele, De Minicis

AU - Osterreicher, Christoph H

AU - Colmenero, Jordi

AU - Bataller, Ramon

AU - Schwabe, Robert F

PY - 2010

Y1 - 2010

N2 - BACKGROUND ; AIMS: c-Jun N-terminal kinase (JNK) is activated by multiple profibrogenic mediators; JNK activation occurs during toxic, metabolic, and autoimmune liver injury. However, its role in hepatic fibrogenesis is unknown. METHODS: JNK phosphorylation was detected by immunoblot analysis and confocal immunofluorescent microscopy in fibrotic livers from mice after bile duct ligation (BDL) or CCl(4) administration and in liver samples from patients with chronic hepatitis C and non-alcoholic steatohepatitis. Fibrogenesis was investigated in mice given the JNK inhibitor SP600125 and in JNK1- and JNK2-deficient mice following BDL or CCl(4) administration. Hepatic stellate cell (HSC) activation was determined in primary mouse HSCs incubated with pan-JNK inhibitors SP600125 and VIII. RESULTS: JNK phosphorylation was strongly increased in livers of mice following BDL or CCl(4) administration as well as in human fibrotic livers, occurring predominantly in myofibroblasts. In vitro, pan-JNK inhibitors prevented transforming growth factor (TGF) beta-, platelet-derived growth factor-, and angiotensin II-induced murine HSC activation and decreased platelet-derived growth factor and TGF-beta signaling in human HSCs. In vivo, pan-JNK inhibition did not affect liver injury but significantly reduced fibrosis after BDL or CCl(4). JNK1-deficient mice had decreased fibrosis after BDL or CCl(4), whereas JNK2-deficient mice displayed increased fibrosis after BDL but fibrosis was not changed after CCl(4). Moreover, patients with chronic hepatitis C who displayed decreased fibrosis in response to the angiotensin receptor type 1 blocker losartan showed decreased JNK phosphorylation. CONCLUSIONS: JNK is involved in HSC activation and fibrogenesis and represents a potential target for antifibrotic treatment approaches.

AB - BACKGROUND ; AIMS: c-Jun N-terminal kinase (JNK) is activated by multiple profibrogenic mediators; JNK activation occurs during toxic, metabolic, and autoimmune liver injury. However, its role in hepatic fibrogenesis is unknown. METHODS: JNK phosphorylation was detected by immunoblot analysis and confocal immunofluorescent microscopy in fibrotic livers from mice after bile duct ligation (BDL) or CCl(4) administration and in liver samples from patients with chronic hepatitis C and non-alcoholic steatohepatitis. Fibrogenesis was investigated in mice given the JNK inhibitor SP600125 and in JNK1- and JNK2-deficient mice following BDL or CCl(4) administration. Hepatic stellate cell (HSC) activation was determined in primary mouse HSCs incubated with pan-JNK inhibitors SP600125 and VIII. RESULTS: JNK phosphorylation was strongly increased in livers of mice following BDL or CCl(4) administration as well as in human fibrotic livers, occurring predominantly in myofibroblasts. In vitro, pan-JNK inhibitors prevented transforming growth factor (TGF) beta-, platelet-derived growth factor-, and angiotensin II-induced murine HSC activation and decreased platelet-derived growth factor and TGF-beta signaling in human HSCs. In vivo, pan-JNK inhibition did not affect liver injury but significantly reduced fibrosis after BDL or CCl(4). JNK1-deficient mice had decreased fibrosis after BDL or CCl(4), whereas JNK2-deficient mice displayed increased fibrosis after BDL but fibrosis was not changed after CCl(4). Moreover, patients with chronic hepatitis C who displayed decreased fibrosis in response to the angiotensin receptor type 1 blocker losartan showed decreased JNK phosphorylation. CONCLUSIONS: JNK is involved in HSC activation and fibrogenesis and represents a potential target for antifibrotic treatment approaches.

KW - Animals

KW - Humans

KW - Angiotensin II pharmacology

KW - Anthracenes pharmacology

KW - Carrier Proteins antagonists

KW - inhibitors

KW - Cell Division drug effects

KW - Cells, Cultured

KW - Disease Models, Animal

KW - Fatty Liver drug therapy

KW - Fibroblasts enzymology

KW - Hepatic Stellate Cells enzymology

KW - Hepatitis C, Chronic drug therapy

KW - Liver Cirrhosis drug therapy

KW - Membrane Glycoproteins antagonists

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Mice, Mutant Strains

KW - Mitogen-Activated Protein Kinase 9 metabolism

KW - Phosphorylation physiology

KW - Platelet-Derived Growth Factor pharmacology

KW - Protein Kinase Inhibitors pharmacology

KW - Transforming Growth Factor beta pharmacology