Tribbles homologue 3 stimulates canonical TGF-β signalling to regulate fibroblast activation and tissue fibrosis
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25603829
DOI
10.1136/annrheumdis-2014-206234
PII: S0003-4967(24)01958-7
Knihovny.cz E-resources
- Keywords
- Fibroblasts, Systemic Sclerosis, Treatment,
- MeSH
- Antibiotics, Antineoplastic toxicity MeSH
- Bleomycin toxicity MeSH
- Adult MeSH
- Fibroblasts metabolism MeSH
- Fibrosis chemically induced genetics MeSH
- Gene Knockdown Techniques MeSH
- Gene Knock-In Techniques MeSH
- Immunohistochemistry MeSH
- Collagen metabolism MeSH
- Skin Diseases chemically induced genetics MeSH
- Cells, Cultured MeSH
- Real-Time Polymerase Chain Reaction MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- Smad3 Protein metabolism MeSH
- Protein Serine-Threonine Kinases antagonists & inhibitors genetics metabolism MeSH
- Cell Cycle Proteins genetics metabolism MeSH
- Receptors, Transforming Growth Factor beta MeSH
- Repressor Proteins genetics metabolism MeSH
- Aged MeSH
- Signal Transduction genetics MeSH
- Dermis cytology MeSH
- Case-Control Studies MeSH
- Scleroderma, Systemic genetics metabolism MeSH
- Receptor, Transforming Growth Factor-beta Type I MeSH
- Transforming Growth Factor beta metabolism MeSH
- Animals MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Mice MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antibiotics, Antineoplastic MeSH
- Bleomycin MeSH
- Collagen MeSH
- Smad3 Protein MeSH
- Protein Serine-Threonine Kinases MeSH
- Cell Cycle Proteins MeSH
- Receptors, Transforming Growth Factor beta MeSH
- Repressor Proteins MeSH
- Receptor, Transforming Growth Factor-beta Type I MeSH
- Transforming Growth Factor beta MeSH
- TRB3 protein, mouse MeSH Browser
- TRIB3 protein, human MeSH Browser
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.
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