期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 29, 期 2, 页码 557-570出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2016121362
关键词
-
资金
- National Health and Medical Research Council of Australia [632688, 1046647]
TGF-beta is a key profibrotic factor, but targeting TGF-beta to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF-beta signaling by preventing downstream profibrotic interaction of beta-catenin with T cell factor (TCF), thereby enhancing the interaction of beta-catenin with Foxo, a transcription factor that controls differentiation of TGF-beta induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF-beta. In iTregs derived from EL4 T cells treated with recombinant human TGF-beta 1 (rhTGF-beta 1) in vitro, inhibition of beta-catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of beta-catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of beta-catenin expression positively correlated with the level of Foxo1 binding to the Foxp3 promoter and Foxo transcriptional activity. T cell fate mapping in Foxp3gfp Ly5.1/5.2 mice revealed that coadministration of rhTGF-beta 1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF-beta 1 treatment alone. Coadministration of rhTGF-beta 1 with ICG-001 also increased the number of Tregs and reduced inflammation and fibrosis in the kidney fibrosis models of unilateral ureteric obstruction and ischemia-reperfusion injury. Notably, ICG-001 prevented the fibrosis in distant organs (lung and liver) caused by rhTGF-beta 1. Together, our results show that diversion of beta-catenin from TCF- to Foxo-mediated transcription inhibits the beta-catenin/TCF-mediated profibrotic effects of TGF-beta while enhancing the beta-catenin/Foxo-mediated anti-inflammatory effects. Targeting beta-catenin/Foxomay be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure.
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