1. Tribbles homologue 3 stimulates canonical TGF-β signalling to regulate fibroblast activation and tissue fibrosis.
- Author
-
Tomcik M, Palumbo-Zerr K, Zerr P, Sumova B, Avouac J, Dees C, Distler A, Becvar R, Distler O, Schett G, Senolt L, and Distler JH
- Subjects
- Adult, Aged, Animals, Antibiotics, Antineoplastic toxicity, Bleomycin toxicity, Case-Control Studies, Cell Cycle Proteins metabolism, Cells, Cultured, Collagen metabolism, Dermis cytology, Disease Models, Animal, Female, Fibrosis chemically induced, Fibrosis genetics, Gene Knock-In Techniques, Gene Knockdown Techniques, Humans, Immunohistochemistry, Male, Mice, Middle Aged, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Real-Time Polymerase Chain Reaction, Receptor, Transforming Growth Factor-beta Type I, Receptors, Transforming Growth Factor beta, Repressor Proteins metabolism, Scleroderma, Systemic metabolism, Signal Transduction genetics, Skin Diseases chemically induced, Skin Diseases genetics, Young Adult, Cell Cycle Proteins genetics, Fibroblasts metabolism, Protein Serine-Threonine Kinases antagonists & inhibitors, Repressor Proteins genetics, Scleroderma, Systemic genetics, Smad3 Protein metabolism, Transforming Growth Factor beta metabolism
- Abstract
Objectives: Tribbles homologue 3 (TRB3) is a pseudokinase that modifies the activation of various intracellular signalling pathways to control fundamental processes extending from mitosis and cell activation to apoptosis and modulation of gene expression. Here, we aimed to analyse the role of TRB3 in fibroblast activation in systemic sclerosis (SSc)., Methods: The expression of TRB3 was quantified by quantitative PCR, western blot and immunohistochemistry. The role of TRB3 was analysed in cultured fibroblasts and in experimental fibrosis using small interfering RNA (siRNA)-mediated knockdown and overexpression of TRB3., Results: TRB3 expression was increased in fibroblasts of patients with SSc and in murine models of SSc in a transforming growth factor-β (TGF-β)/Smad-dependent manner. Overexpression of TRB3 stimulated canonical TGF-β signalling and induced an activated phenotype in resting fibroblasts. In contrast, knockdown of TRB3 reduced the profibrotic effects of TGF-β and decreased the collagen synthesis. Moreover, siRNA-mediated knockdown of TRB3 exerted potent antifibrotic effects and ameliorated bleomycin as well as constitutively active TGF-β receptor I-induced fibrosis with reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation., Conclusions: The present study characterises TRB3 as a novel profibrotic mediator in SSc. TGF-β induces TRB3, which in turn activates canonical TGF-β/Smad signalling and stimulates the release of collagen, thereby inducing a positive feedback loop that may contribute to aberrant TGF-β signalling in SSc., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
- Published
- 2016
- Full Text
- View/download PDF