| Summary: | 碩士 === 臺北醫學大學 === 醫學科學研究所 === 98 === Several evidences suggest that connective tissue growth factor (CTGF) overproduction underlies the development of lung fibrosis. Development of lung fibrosis is characterized by excessive deposition of collagens in the lung interstitium. Mixed linage kinase 3 (MLK3) can be regulated by Rac and then activate downstream molecule JNK, which in turns activates transcription factor activator protein-1(AP-1). In this study, we found that CTGF could induce collagen expression, and overexpression of wild-type MLK3 also enhanced collagen expression. Overexpressed dominant negative of MLK3 (MLK3 DN) and K252a (a MLK3 inhibtor) concentration-dependently inhibited CTGF-induced collagen expression. CTGF also induced phosphorylation of MLK3 at Thr277/Ser281. Pretreatment of SP600125 (a JNK inhibtor) or transfection with JNK1/2 DN decreased CTGF-induced collagen expression in WI38 fibroblasts. CTGF also induced JNK phosphorylation in time-dependent manner. We also found that curcumin (an AP-1 inhibtor) reduced CTGF-induced collagen expression in a concentration-dependent manner. CTGF induced increase in c-Jun phosphorylation and AP-1-luciferase activity and also increased binding of AP-1 to collagen promoter region. In addition, CTGF induced increases in Rac1 activity, and RacN17 DN inhibit CTGF-induced collagen expression, MLK3 phosphorylation and JNK phosphorylation. CTGF-mediated AP-1 activation was inhibited by RacN17 DN、MLK3 DN and JNK1/2 DN. Taken together, these results suggest that the Rac1/MLK3-dependent JNK/AP-1 signaling pathway plays an important roles in CTGF-induced collagen expression in WI38 fibroblasts.
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