TGFβ1 Controls PPARγ Expression, Transcriptional Potential, and Activity, in Part, through Smad3 Signaling in Murine Lung Fibroblasts.
TGFβ1 Controls PPARγ Expression, Transcriptional Potential, and Activity, in Part, through Smad3 Signaling in Murine Lung Fibroblasts.
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DOI：
10.1155/2012/375876
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发表时间：
2012
期刊：
影响因子：
2.9
通讯作者：
Roman J
中科院分区：
文献类型：
--
作者：
Ramirez A;Ballard EN;Roman J
转化生长因子β1（TGFβ1）通过激活静止的成纤维细胞成为肌成纤维细胞和增加细胞外基质的表达等机制促进纤维化。最近的研究表明，过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ）是TGFβ1诱导的纤维化事件的负调控因子。然而，我们假设由PPARγ介导的抗纤维化途径受到TGFβ1的影响，导致纤维化发生失衡。与此一致，原代小鼠原代肺成纤维细胞对TGFβ1的应答是持续下调PPARγ转录物。这种作用在Smad 3缺陷的肺成纤维细胞中减弱，Smad 3是一种介导TGFβ1许多作用的转录因子。TGFβ1刺激原代肺成纤维细胞中PPARγ基因启动子的激活，并诱导其磷酸化。然后在含有PPARγ响应性荧光素酶报告基因的NIH/3 T3成纤维细胞中测试了TGFβ1调节PPARγ转录活性的能力。在这些细胞中，用组成型活性TGFβ1受体转基因刺激TGFβ1信号，减弱了由PPARγ激活剂曲格列酮诱导的PPARγ依赖性报告基因表达。过表达的PPARγ阻止了TGFβ1对曲格列酮诱导的PPARγ依赖性基因转录的抑制，而共表达的PPARγ和Smad 3转基因重现了TGFβ1的作用。我们的结论是，PPARγ的调节由TGFβ1控制，部分通过Smad 3信号，涉及调节PPARγ的表达和转录潜力。
Transforming growth factor β1 (TGFβ1) promotes fibrosis by, among other mechanisms, activating quiescent fibroblasts into myofibroblasts and increasing the expression of extracellular matrices. Recent work suggests that peroxisome proliferator-activated receptor γ (PPARγ) is a negative regulator of TGFβ1-induced fibrotic events. We, however, hypothesized that antifibrotic pathways mediated by PPARγ are influenced by TGFβ1, causing an imbalance towards fibrogenesis. Consistent with this, primary murine primary lung fibroblasts responded to TGFβ1 with a sustained downregulation of PPARγ transcripts. This effect was dampened in lung fibroblasts deficient in Smad3, a transcription factor that mediates many of the effects of TGFβ1. Paradoxically, TGFβ1 stimulated the activation of the PPARγ gene promoter and induced the phosphorylation of PPARγ in primary lung fibroblasts. The ability of TGFβ1 to modulate the transcriptional activity of PPARγ was then tested in NIH/3T3 fibroblasts containing a PPARγ-responsive luciferase reporter. In these cells, stimulation of TGFβ1 signals with a constitutively active TGFβ1 receptor transgene blunted PPARγ-dependent reporter expression induced by troglitazone, a PPARγ activator. Overexpression of PPARγ prevented TGFβ1 repression of troglitazone-induced PPARγ-dependent gene transcription, whereas coexpression of PPARγ and Smad3 transgenes recapitulated the TGFβ1 effects. We conclude that modulation of PPARγ is controlled by TGFβ1, in part through Smad3 signals, involving regulation of PPARγ expression and transcriptional potential.
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DOI：
10.3109/08977194.2011.595714
发表时间：
2011-10
期刊：
Growth factors (Chur, Switzerland)
影响因子：
--
作者：
Biernacka A;Dobaczewski M;Frangogiannis NG
通讯作者：
Frangogiannis NG
DOI：
10.1152/ajpgi.00200.2006
发表时间：
2007-01-01
影响因子：
4.5
作者：
Zheng, Shizhong;Chen, Anping
通讯作者：
Chen, Anping
影响因子：
6
作者：
Ramirez, AM;Takagawa, S;Roman, J
通讯作者：
Roman, J
影响因子：
8.8
作者：
Ramirez, A. M.;Shen, Z.;Roman, J.
通讯作者：
Roman, J.
影响因子：
7.4
作者：
Blanquicett, Carmelo;Kang, Bum-Yong;Ritzenthaler, Jeffrey D.;Jones, Dean P.;Hart, C. Michael
通讯作者：
Hart, C. Michael