Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition.
OBJECTIVE
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.
Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Johannes
J
Kluwe
Jean-Philippe
JP
Pradere
Geum-Youn
GY
Gwak
Ali
A
Mencin
Samuele
S
De Minicis
Christoph H
CH
Osterreicher
Jordi
J
Colmenero
Ramon
R
Bataller
Robert F
RF
Schwabe
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000201:enzymology* / Q000473:pathology; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000873:Anthracenes; D002352:Carrier Proteins; C505618:JAMP protein, mouse; C541074:JKAMP protein, human; D008562:Membrane Glycoproteins; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; C432165:pyrazolanthrone; D048056:Mitogen-Activated Protein Kinase 9