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Association of β-catenin with P-Smad3 but not LEF-1 dissociates in vitro profibrotic from anti-inflammatory effects of TGF-β1
- Source :
- Journal of Cell Science. 126:67-76
- Publication Year :
- 2013
- Publisher :
- The Company of Biologists, 2013.
-
Abstract
- Summary Transforming growth factor β1 (TGF-β1) is known to be both anti-inflammatory and profibrotic. Cross-talk between TGF-β/Smad and Wnt/β-catenin pathways in epithelial–mesenchymal transition (EMT) suggests a specific role for β-catenin in profibrotic effects of TGF-β1. However, no such mechanistic role has been demonstrated for β-catenin in the anti-inflammatory effects of TGF-β1. In the present study, we explored the role of β-catenin in the profibrotic and anti-inflammatory effects of TGF-β1 by using a cytosolic, but not membrane, β-catenin knockdown chimera (F-TrCP-Ecad) and the β-catenin/CBP inhibitor ICG-001. TGF-β1 induced nuclear Smad3/β-catenin complex, but not β-catenin/LEF-1 complex or TOP-flash activity, during EMT of C1.1 (renal tubular epithelial) cells. F-TrCP-Ecad selectively degraded TGF-β1-induced cytoplasmic β-catenin and blocked EMT of C1.1 cells. Both F-TrCP-Ecad and ICG-001 blocked TGF-β1-induced Smad3/β-catenin and Smad reporter activity in C1.1 cells, suggesting that TGF-β1-induced EMT depends on β-catenin binding to Smad3, but not LEF-1 downstream of Smad3, through canonical Wnt. In contrast, in J774 macrophages, the β-catenin level was low and was not changed by interferon-γ (IFN-γ) or lipopolysaccharide (LPS) with or without TGF-β1. TGF-β1 inhibition of LPS-induced TNF-α and IFN-γ-stimulated inducible NO synthase (iNOS) expression was not affected by F-TrCP-Ecad, ICG-001 or by overexpression of wild-type β-catenin in J774 cells. Inhibition of β-catenin by either F-TrCP-Ecad or ICG-001 abolished LiCl-induced TOP-flash, but not TGF-β1-induced Smad reporter, activity in J774 cells. These results demonstrate for the first time that β-catenin is required as a co-factor of Smad in TGF-β1-induced EMT of C1.1 epithelial cells, but not in TGF-β1 inhibition of macrophage activation. Targeting β-catenin may dissociate the TGF-β1 profibrotic and anti-inflammatory effects.
- Subjects :
- medicine.medical_specialty
Epithelial-Mesenchymal Transition
Lymphoid Enhancer-Binding Factor 1
Blotting, Western
Anti-Inflammatory Agents
SMAD
Biology
Cell Line
Transforming Growth Factor beta1
Mice
Internal medicine
medicine
Animals
Immunoprecipitation
Smad3 Protein
beta Catenin
Gene knockdown
Reverse Transcriptase Polymerase Chain Reaction
Wnt signaling pathway
Cell Biology
In vitro
Cell biology
Blot
Endocrinology
Microscopy, Fluorescence
Cell culture
Catenin
Protein Binding
Transforming growth factor
Subjects
Details
- ISSN :
- 14779137 and 00219533
- Volume :
- 126
- Database :
- OpenAIRE
- Journal :
- Journal of Cell Science
- Accession number :
- edsair.doi.dedup.....1b71fc61da5e5e5689e0e19ae750cb30