Association of ß-catenin with P-Smad3 but not LEF-1 dissociates in vitro profibrotic from anti-inflammatory effects of TGF-ß1.
J Cell Sci
; 126(Pt 1): 67-76, 2013 Jan 01.
Article
en En
| MEDLINE
| ID: mdl-23203799
Transforming growth factor ß1 (TGF-ß1) is known to be both anti-inflammatory and profibrotic. Cross-talk between TGF-ß/Smad and Wnt/ß-catenin pathways in epithelial-mesenchymal transition (EMT) suggests a specific role for ß-catenin in profibrotic effects of TGF-ß1. However, no such mechanistic role has been demonstrated for ß-catenin in the anti-inflammatory effects of TGF-ß1. In the present study, we explored the role of ß-catenin in the profibrotic and anti-inflammatory effects of TGF-ß1 by using a cytosolic, but not membrane, ß-catenin knockdown chimera (F-TrCP-Ecad) and the ß-catenin/CBP inhibitor ICG-001. TGF-ß1 induced nuclear Smad3/ß-catenin complex, but not ß-catenin/LEF-1 complex or TOP-flash activity, during EMT of C1.1 (renal tubular epithelial) cells. F-TrCP-Ecad selectively degraded TGF-ß1-induced cytoplasmic ß-catenin and blocked EMT of C1.1 cells. Both F-TrCP-Ecad and ICG-001 blocked TGF-ß1-induced Smad3/ß-catenin and Smad reporter activity in C1.1 cells, suggesting that TGF-ß1-induced EMT depends on ß-catenin binding to Smad3, but not LEF-1 downstream of Smad3, through canonical Wnt. In contrast, in J774 macrophages, the ß-catenin level was low and was not changed by interferon-γ (IFN-γ) or lipopolysaccharide (LPS) with or without TGF-ß1. TGF-ß1 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 ß-catenin in J774 cells. Inhibition of ß-catenin by either F-TrCP-Ecad or ICG-001 abolished LiCl-induced TOP-flash, but not TGF-ß1-induced Smad reporter, activity in J774 cells. These results demonstrate for the first time that ß-catenin is required as a co-factor of Smad in TGF-ß1-induced EMT of C1.1 epithelial cells, but not in TGF-ß1 inhibition of macrophage activation. Targeting ß-catenin may dissociate the TGF-ß1 profibrotic and anti-inflammatory effects.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteína smad3
/
Beta Catenina
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Factor de Unión 1 al Potenciador Linfoide
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Factor de Crecimiento Transformador beta1
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Antiinflamatorios
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
J Cell Sci
Año:
2013
Tipo del documento:
Article
País de afiliación:
Australia