TGF-b is a key profibrotic factor, but targeting TGF-b to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF-b signaling by preventing downstream profibrotic interaction of b-catenin with T cell factor (TCF), thereby enhancing the interaction of b-catenin with Foxo, a transcription factor that controls differentiation of TGF-b induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF-b. In iTregs derived from EL4 T cells treated with recombinant human TGF-b1 (rhTGF-b1) in vitro, inhibition of b-catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of b-catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of b-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-b1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF-b1 treatment alone. Coadministration of rhTGF-b1 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-b1. Together, our results show that diversion of b-catenin from TCF- to Foxo-mediated transcription inhibits the b-catenin/TCF-mediated profibrotic effects of TGF-b while enhancing the b-catenin/Foxo-mediated anti-inflammatory effects. Targeting b-catenin/Foxo may be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure.
CITATION STYLE
Qiao, X., Rao, P., Zhang, Y., Liu, L., Pang, M., Wang, H., … Harris, D. C. H. (2018). Redirecting TGF-b Signaling through the b-Catenin/ Foxo Complex Prevents Kidney Fibrosis. Journal of the American Society of Nephrology, 29(2), 557–570. https://doi.org/10.1681/ASN.2016121362
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