Modulation of Hepatic Fibrosis by c-Jun-N-Terminal Kinase Inhibition

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 immuno-fluorescent microscopy in fibrotic livers from mice after bile duct ligation (BDL) Or CCl4 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 CCl4 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 CCl4 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 CCl4, JNK1-deficient mice had decreased fibrosis after BDL Or CCl4, whereas JNK2-deficient mice displayed increased fibrosis after BDL but fibrosis was not changed after CCl4. Moreover, patients with chronic hepatitis C who displayed decreased fibrosis in response to the angiotensin receptor type I blocker losartan showed decreased JNK phosphorylation. CONCLUSIONS: JNK is involved in HSC activation and fibrogenesis and represents a potential target for antifibrotic treatment approaches.