Requirement of Transforming Growth Factor β-Activated Kinase 1 for Transforming Growth Factor β-Induced α-Smooth Muscle Actin Expression and Extracellular Matrix Contraction in Fibroblasts

被引:66
作者
Shi-wen, Xu [2 ]
Parapuram, Sunil K.
Pala, Daphne
Chen, Yunliang [3 ]
Carter, David E. [4 ]
Eastwood, Mark [3 ]
Denton, Christopher P. [2 ]
Abraham, David J. [2 ]
Leask, Andrew [1 ]
机构
[1] Univ Western Ontario, CIHR Grp Skeletal Dev Remodeling, Dept Physiol & Pharmacol, Schulich Sch oi Med & Dent, London, ON N6A 5C1, Canada
[2] UCL, London, England
[3] Univ Westminster, London W1R 8AL, England
[4] London Reg Genom Ctr, London, ON, Canada
来源
ARTHRITIS AND RHEUMATISM | 2009年 / 60卷 / 01期
基金
加拿大健康研究院;
关键词
FOCAL ADHESION KINASE; TGF-BETA; FIBROTIC RESPONSE; PHOSPHORYLATION; MYOFIBROBLAST; SCLERODERMA; CCN2;
D O I
10.1002/art.24223
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective. Fibrosis is believed to occur through normal tissue remodeling failing to terminate. Tissue repair intimately involves the ability of fibroblasts to contract extracellular matrix (ECM), and enhanced ECM contraction is a hallmark of fibrotic cells in various conditions, including scleroderma. Some fibrogenic transcriptional responses to transforming growth factor beta (TGF beta), including alpha-smooth muscle actin (alpha-SMA) expression and ECM contraction, require focal adhesion kinase/Src (FAK/Src). The present study was undertaken to assess whether TGF beta-activated kinase I (TAK1) acts downstream of FAK/Src to mediate fibrogenic responses in fibroblasts. Methods. We used microarray, real-time polymerase chain reaction, Western blot, and collagen gel contraction assays to assess the ability of wild-type and TAK1-knockout fibroblasts to respond to TGF beta 1. Results. The ability of TGF to induce TAK1 was blocked by the FAK/Src inhibitor PP2. JNK phosphorylation in response to TGF beta 1 was impaired in the absence of TAK1. TGF beta could not induce matrix contraction or expression of a group of fibrotic genes, including alpha-SMA, in the absence of TAK1. Conclusion. These results suggest that TAK1 operates downstream of FAK/Src in mediating fibrogenic responses and that targeting of TAK1 may be a viable antifibrotic strategy in the treatment of certain disorders, including scleroderma.
引用
收藏
页码:234 / 241
页数:8
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