Connective tissue growth factor induces collagen I expression in human lung fibroblasts through the Rac1/MLK3/JNK/AP-1 pathway

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

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

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 α-smooth muscle actin (α-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. agen I expression may help elucidate the role of CTGF in lung fibrosis.

Original languageEnglish
Pages (from-to)2823-2833
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1833
Issue number12
DOIs
Publication statusPublished - Dec 2013

Keywords

  • Collagen I
  • Connective tissue growth factor
  • Fibroblasts
  • Lung fibrosis
  • Signal transduction

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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