Connective tissue growth factor induces collagen I expression in human lung fibroblasts through the Rac1/MLK3/JNK/AP-1 pathway
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- 作者：Chien-Huang Lin ; Ming-Chih Yu ; Wan-Hsuan Tung ; Tzu-Ting Chen ; Chung-Chi Yu ; Chih-Ming Weng ; Yan-Jyu Tsai ; Kua-Jen Bai ; Chuang-Ye Hong ; Ming-Hsien Chien ; Bing-Chang Chen
- 关键词：AP-1 ; activator protein-1 ; ASK1 ; apoptosis signal-regulating kinase 1 ; c/EBP尾 ; CCAAT/enhancer-binding protein 尾 ; ChIP ; chromatin immunoprecipitation ; CTGF ; connective tissue growth factor ; ECM ; extracellular matrix ; ERK ; extracellular signal-regulated kinase ; FCS ; fetal calf serum ; IL-6 ; interleukin-6 ; JAK ; Janus kinase ; JNK ; c-Jun N-terminal kinase ; MAPKKK ; MAPK kinase kinase ; MAPKs ; mitogen-activated protein kinases ; MEM ; Minimum Essential Medium ; MLB ; magnesium lysis buffer ; MLK3 ; mixed-lin
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
- 出版年：December, 2013
- 年：2013
- 卷：1833
- 期：12
- 页码：2823-2833
- 全文大小：1715 K
文摘
Connective tissue growth factor (CTGF) plays an important role in lung fibrosis. In this study, we investigated the role of Rac1, mixed-lineage kinase 3 (MLK3), c-Jun N-terminal kinase (JNK), and activator protein-1 (AP-1) in CTGF-induced collagen I expression in human lung fibroblasts. CTGF caused concentration- and time-dependent increases in collagen I expression. CTGF-induced collagen I expression was inhibited by the dominant negative mutant (DN) of Rac1 (RacN17), MLK3DN, MLK3 inhibitor (K252a), JNK1DN, JNK2DN, a JNK inhibitor (SP600125), and an AP-1 inhibitor (curcumin). Treatment of cells with CTGF caused activation of Rac1, MLK3, JNK, and AP-1. The CTGF-induced increase in MLK3 phosphorylation was inhibited by RacN17. Treatment with RacN17 and the MLK3DN inhibited CTGF-induced JNK phosphorylation. CTGF caused increases in c-Jun phosphorylation and the recruitment of c-Jun and c-Fos to the collagen I promoter. Furthermore, stimulation of cells with the CTGF resulted in increases in AP-1-luciferase activity; this effect was inhibited by Rac1N17, MLK3DN, JNK1DN, and JNK2DN. Moreover, CTGF-induced 伪-smooth muscle actin (伪-SMA) expression was inhibited by the procollagen I small interfering RNA (siRNA). These results suggest for the first time that CTGF acting through Rac1 activates the MLK3/JNK signaling pathway, which in turn initiates AP-1 activation and recruitment of c-Jun and c-Fos to the collagen I promoter and ultimately induces collagen I expression in human lung fibroblasts.