Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition.
Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition.
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DOI：
10.1053/j.gastro.2009.09.015
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发表时间：
2010-01
期刊：
影响因子：
29.4
通讯作者：
Schwabe RF
中科院分区：
文献类型：
--
作者：
Kluwe J;Pradere JP;Gwak GY;Mencin A;De Minicis S;Osterreicher CH;Colmenero J;Bataller R;Schwabe RF
C-Jun氨基末端激酶(JNK)被多种促纤维化介质激活，在中毒性、代谢性和自身免疫性肝损伤过程中激活。然而，它在肝纤维化形成中的作用尚不清楚。用免疫印迹分析和共聚焦免疫荧光显微镜检测了胆管结扎(BDL)和四氯化碳(CCl_4)注射后小鼠肝纤维化以及慢性丙型肝炎和非酒精性脂肪性肝炎患者肝组织中JNK的磷酸化。在给予JNK抑制剂SP600125的小鼠中，以及在BDL或CCl4给药后JNK1和JNK2缺陷的小鼠中，研究了纤维化的形成。用PAN-JNK抑制剂SP600125和VIII孵育的原代小鼠肝星状细胞(HSC)被检测到激活。BDL或CCl4处理的小鼠肝脏和人肝纤维化肝组织中JNK磷酸化显著增加，主要发生在肌成纤维细胞中。在体外，PAN-JNK抑制剂可抑制转化生长因子β、血小板衍生生长因子和血管紧张素II诱导的小鼠肝星状细胞活化，并降低转化生长因子和转化生长因子β信号转导。在体内，PAN-JNK抑制不影响肝损伤，但显著减少BDL或CCl4后的纤维化。JNK1缺陷小鼠在BDL或CCl4后纤维化减轻，而JNK2缺陷小鼠BDL后纤维化增加，但CCl4后纤维化没有改变。此外，对血管紧张素受体1型阻滞剂氯沙坦有反应的慢性丙型肝炎患者的肝纤维化程度降低，其JNK的磷酸化程度也降低。JNK参与了HSC的激活和纤维化的形成，是抗纤维化治疗的潜在靶点。
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 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. 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)β-, platelet-derived growth factor (PDGF)-, and angiotensin II-induced murine HSC activation and decreased PDGF and TGFβ 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 1 blocker losartan showed decreased JNK phosphorylation. JNK is involved in HSC activation and fibrogenesis and represents a potential target for antifibrotic treatment approaches.