Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Gastroenterology. 2010 Jan;138(1):347-59. doi: 10.1053/j.gastro.2009.09.015. Epub 2009 Sep 24.
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.
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.
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.
JNK is involved in HSC activation and fibrogenesis and represents a potential target for antifibrotic treatment approaches.
c-Jun N-末端激酶（JNK）可被多种促纤维化介质激活；JNK 的激活发生在毒性、代谢和自身免疫性肝损伤期间。然而，其在肝纤维化形成中的作用尚不清楚。
通过免疫印迹分析和共聚焦免疫荧光显微镜检测在胆管结扎（BDL）或 CCl4 给药后纤维化小鼠的肝脏以及慢性丙型肝炎和非酒精性脂肪性肝炎患者的肝组织中 JNK 的磷酸化。在给予 JNK 抑制剂 SP600125 的小鼠以及 BDL 或 CCl4 给药后 JNK1 和 JNK2 缺陷型小鼠中研究纤维化。在与 pan-JNK 抑制剂 SP600125 和 VIII 孵育的原代小鼠肝星状细胞（HSC）中测定 HSC 的激活。
BDL 或 CCl4 给药后以及人类纤维化肝脏中 JNK 的磷酸化明显增加，主要发生在肌成纤维细胞中。在体外，pan-JNK 抑制剂可预防转化生长因子（TGF）β、血小板衍生生长因子和血管紧张素 II 诱导的小鼠 HSC 激活，并降低人 HSCs 中血小板衍生生长因子和 TGF-β信号。在体内，pan-JNK 抑制不影响肝损伤，但可显著减少 BDL 或 CCl4 后的纤维化。BDL 或 CCl4 后 JNK1 缺陷型小鼠的纤维化减少，而 JNK2 缺陷型小鼠的纤维化增加，但 CCl4 后纤维化无变化。此外，对血管紧张素受体 1 阻滞剂氯沙坦有反应性纤维化减少的慢性丙型肝炎患者 JNK 磷酸化减少。
JNK 参与 HSC 的激活和纤维化形成，是抗纤维化治疗方法的潜在靶点。
